leptin

C Subfamily
CC Subfamily
CXC Subfamily
CX3C Subfamily

Chemokines

gp130 (IL6ST) shared
IL13RA1 shared
IL3RB (CSF2RB) shared
ILRG shared

interleukin 18
interleukin 18 proprotein
interleukin 1 alpha
interleukin 1, alpha proprotein
interleukin 1 beta
interleukin 1, beta proprotein

interleukin 17
interleukin 17b
interleukin 17E
interleukin 17E isoform 1

IL-1 Family /IL-17 Family

interleukin 10
interleukin 19
interleukin 19 isoform 2
interleukin 20
interleukin 22
interleukin 24
interleukin 24 isoform 1
interleukin 28A
interleukin 28B
interleukin 29

IL-10 Family

interferon alpha family, gene 1
interferon, alpha 1
interferon beta
interferon, beta 1
interferon epsilon 1
interferon, epsilon 1
interferon gamma
interferon, gamma
interferon kappa
interferon, kappa
interferon, omega 1

Interferon Family

CSF1 Egf Flt3l
FLT3LG HGF Kitl
KITLG Pdgfa PDGFB
PDGFC Pdgfd PLEKHQ1
VEGF Vegfa VEGFB
VEGFC

PDGF Family

AMH Bmp2 Bmp7
GDF5 Inhba INHBB
INHBC INHBE Tgfb1
TGFB2 TGFB3

TGF-β Family

CD40LG Eda Fasl
FASLG Lta LTB
TNF Tnfsf10 Tnfsf11
TNFSF12 Tnfsf13 TNFSF13B
Tnfsf14 TNFSF18 TNFSF4
TNFSF7 TNFSF8 TNFSF9

TNF Family

LEPTIN

LATEST LITERATURE

1: Digestive diseases and sciences, 2010 Sep 8, 75(10)
Impact of Obesity and Leptin on Protein Expression Profiles in Mouse Colon.

[Abstract]BACKGROUND: Elevated leptin levels in obesity are associated with increased risk of colon pathology, implicating leptin signaling in colon disease. However, leptin-regulated processes in the colon are currently uncharacterized. Previously, we demonstrated that leptin receptors are expressed on colon epithelium and that increased adiposity and elevated plasma leptin in rats are associated with perturbed metabolism in colon tissue. Thus, we hypothesize that obesity disrupts expression of proteins regulated by leptin in the colon. METHODS: A proteomic analysis was conducted to investigate firstly, differences in the colon of mice lacking leptin and leptin signaling (ob/ob and db/db, respectively) by comparing protein expression profiles with wild-type mice. Secondly, responses to leptin challenge in wild-type mice and ob/ob mice were compared to identify leptin-regulated proteins and associated cellular processes. RESULTS: Forty proteins were identified with significantly altered expression patterns associated with differences in leptin status in comparisons between all groups of mice. These proteins are associated with calcium binding, cell cycle, cell proliferation, electron transport chain, energy metabolism, protein folding and transport, redox regulation, structural proteins, and proteins involved in transport and regulation of mucus production. CONCLUSIONS: This study provides evidence that obesity and leptin significantly alter protein profiles of a number of proteins linked to cellular processes in colon tissues that may be linked to the increased risk of colon pathology associated with obesity.

2: Proceedings of the National Academy of Sciences of the United States of America, 2010 Sep 7, 13(1)
A sensitive period for environmental regulation of eating behavior and leptin sensitivity.

[Abstract]Western lifestyle contributes to body weight dysregulation. Leptin down-regulates food intake by modulating the activity of neural circuits in the hypothalamic arcuate nucleus (ARC), and resistance to this hormone constitutes a permissive condition for obesity. Physical exercise modulates leptin sensitivity in diet-induced obese rats. The role of other lifestyle components in modulating leptin sensitivity remains elusive. Environmentally enriched mice were used to explore the effects of lifestyle change on leptin production/action and other metabolic parameters. We analyzed adult mice exposed to environmental enrichment (EE), which showed decreased leptin, reduced adipose mass, and increased food intake. We also analyzed 50-d-old mice exposed to either EE (YEE) or physical exercise (YW) since birth, both of which showed decreased leptin. YEE mice showed no change in food intake, increased response to leptin administration, increased activation of STAT3 in the ARC. The YW leptin-induced food intake response was intermediate between young mice kept in standard conditions and YEE. YEE exhibited increased and decreased ratios of excitatory/inhibitory synapses onto alpha-melanocyte-stimulating hormone and agouti-related peptide neurons of the ARC, respectively. We also analyzed animals as described for YEE and then placed in standard cages for 1 mo. They showed no altered leptin production/action but demonstrated changes in excitatory/inhibitory synaptic contacts in the ARC similar to YEE. EE and physical activity resulted in improved insulin sensitivity. In conclusion, EE and physical activity had an impact on feeding behavior, leptin production/action, and insulin sensitivity, and EE affected ARC circuitry. The leptin-hypothalamic axis is maximally enhanced if environmental stimulation is applied during development.

3: Brain & development, 2010 Sep 3, 57(2)
Leptin as a new approach for treatment for autism and epilepsy, a hypothesis with clinical implications.

[Abstract]Background and Objective: The aim of our study was to investigate the interaction between the tumor necrosis factor-alpha (TNF-alpha) gene -308G/A promoter and the leptin receptor (LEPR) gene Lys656Asn polymorphisms and their effects on serum leptin levels in obese subjects. Design: A population of 237 obese patients was analyzed prospectively. Bipolar electrical bioimpedance, a biochemical analysis and serum concentrations of leptin and TNF-alpha were assessed. Results: The number of subjects with both mutations was 21 (8.86%). Subjects carrying the mutant LEPR genotype had higher concentrations of leptin than those with the wild-type LEPR genotype only when they also carried the mutant TNF-alpha genotype (G308A or A308A) (82.7 +/- 63 vs. 147.6 +/- 89 ng/ml; p < 0.05). In subjects with TNF-alpha G308G, multivariate analysis with leptin as a dependent variable revealed fat mass as an independent predictor in the model (F = 15.4; p < 0.05), with an increase of 4.1 ng/ml (95% CI 2.5-5.6) per kilogram of fat mass. The same was seen in subjects with TNF-alpha G308A and A308A genotypes, with an increase in leptin levels of 3.56 ng/ml (95% CI 1.8-5.3) per kilogram fat mass. Conclusion: There is an interaction between TNF-alpha gene G308A promoter and LEPR gene Lys656Asn polymorphisms, with higher concentrations of leptin in the G308A and A308A genotypes combined with the mutant LEPR genotype.

4: Journal of the International AIDS Society, 2010 Sep 7, 13(1)
Association between HIV replication and serum leptin levels: an observational study of a cohort of HIV-1-infected South African women.

[Abstract]ABSTRACT: BACKGROUND: Advanced HIV infection can result in lipoatrophy and wasting, even in the absence of ongoing opportunistic infections, suggesting that HIV may directly affect adipose tissue amount and distribution. METHODS: We assessed the relationship of fat (measured using anthropometry, DEXA, MRI scans) or markers related to glucose and lipid metabolism with viral load in a cross-sectional sample of 83 antiretroviral-naive HIV-1-infected South African women. A multivariable linear model was fitted to log10VL to assess the combined effect of these variables. RESULTS: In addition to higher T cell activation, women with viral load greater than the population median had lower waist circumference, body mass index and subcutaneous abdominal fat, as well as lower serum leptin. We demonstrate that leptin serum levels are inversely associated with viral replication, independent of the amount of adipose tissue. This association is maintained after adjusting for multiple variables associated with disease progression (i.e., cellular activation and innate immunity effector levels). CONCLUSIONS: Our results demonstrate that serum leptin levels are inversely associated with viral replication, independent of disease progression: we postulate that leptin may affect viral replication.

5: Acta obstetricia et gynecologica Scandinavica, 2010 Sep 8, 75(10)
Peripartum serum leptin and soluble leptin receptor levels in women with gestational diabetes.

[Abstract]Abstract The purpose of the study was to clarify the alterations in serum leptin and soluble leptin receptor levels at term and early postpartum in gestational diabetes mellitus (GDM). Twenty women with normal pregnancy and 20 with GDM were recruited and blood samples were taken on the day of delivery and Days 1, 3 and 5 after delivery. Serum leptin levels were significantly higher in women with GDM than in the controls before delivery and decreased significantly after delivery (p < 0.001). After delivery there were no significant differences in serum leptin concentrations between women with GDM and the controls. Serum soluble leptin receptor concentrations did not differ neither between the two groups, nor before or after delivery. Leptin may play a role in GDM through a positive correlation with insulin resistance.

6: Biochemistry and cell biology = Biochimie et biologie cellulaire, 2010 Aug, 88(4)
Effects of leptin on the expression of alpha1 (I) collagen gene in human osteoblast-like MG63 cells.

[Abstract]The objective of this study was to examine the effects of leptin on alpha (alpha) 1 (I) collagen gene expression in a human osteoblast-like MG63 cell line. MG63 cells were incubated with different doses of leptin (10-8, 10-7, and 10-6 mol.L-1) for 24, 48, and 72 h. alpha1 (I) collagen gene expression in MG63 cells was detected by real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), with 17beta-estradiol (17beta-E2) as the positive control. Expression of the alpha1 (I) collagen gene, regulated by leptin, was dose and time dependent, with maximal expression in the 10-7 mol.L-1 group at 72 h of incubation. As a positive control, 17beta-E2 reached its maximal effect in the 10-7mol.L-1 group at 24 h. We conclude that leptin has the ability to up-regulate alpha1 (I) collagen gene expression in MG63 cells, with a more potent effect but a less rapid response than 17beta- E2.

7: Neuroscience and behavioral physiology, 2010 Jul 16, 584(14)
Mechanisms of the Respiratory Activity of Leptin at the Level of the Solitary Tract Nucleus.

[Abstract]Acute experiments on anesthetized laboratory rats were performed to study the effects microinjections of 10(-4) M leptin into the solitary tract nucleus on the extent of the Hering-Breuer inflation reflex in ventilatory reactions to hypercapnia. Local administration of leptin into this area led to inhibition of the Hering-Breuer reflex. The extent of ventilatory responses to hypercapnia, conversely, increased, which may provide evidence that leptin has a modulatory influence on central chemoreceptors. These physiological mechanisms of action probably play a leading role in mediating the stimulatory respiratory effects of leptin at the level of the solitary tract nucleus.

8: Journal of molecular medicine (Berlin, Germany), 2010 Jul 8, 142(1)
Leptin regulates ACE activity in mice.

[Abstract]Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

9: Placenta, 2010 Jul 5, 142(1)
Placental Amino Acid Transport and Placental Leptin Resistance in Pregnancies Complicated by Maternal Obesity.

[Abstract]HYPOTHESIS AND STUDY OBJECTIVES: We hypothesized that maternal obesity is associated with increased placental amino acid transport and hyperleptinemia. Our objectives were to study placental amino acid transport and the effect of leptin on placental amino acid transport in vitro in the setting of maternal obesity. MATERIALS AND METHODS: Seven lean, BMI at entry 22.4, and seven obese, BMI at entry 31.5 (p < 0.001), pregnant women were studied at 39 weeks. We measured baseline and leptin-stimulated placental system A sodium-dependent neutral amino acid transporter (SNAT) activity, placental immunoreactive protein expression of SNAT, leptin and leptin receptor, and maternal and fetal plasma leptin concentrations, with significance set at p 10: Nature reviews. Neurology, 2010 Jul 6, 142(1)
Leptin as a metabolic link to multiple sclerosis.

[Abstract]Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.

11: Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion, 2010 Jul 3, 142(1)
[Leptin: A peptide with therapeutic potential in the obese.]

[Abstract]Obesity is the result of a positive balance between total energy intake and its catabolism. Although many factors are involved in the regulation of energy metabolism, the discovery of leptin led to energy homeostasis being investigated in greater depth. Since its identification, leptin has been considered important in the development of obesity, given its anorexigenic effect and influence on food intake and energy expenditure. Leptin is involved in diverse physiological processes such as energy balance, appetite and body weight control, fat and carbohydrate metabolism, and reproduction. However, to be able to function, this hormone has many specific receptors both centrally (hypothalamus) and peripherally in the skeletal muscle, lungs and kidneys. This study aims to review the key aspects relating leptin to the development of obesity and discusses its potential as an anorectic agent.

12: American journal of physiology. Gastrointestinal and liver physiology, 2010 Jul 1, 479(1)
Insulin- & Leptin-Regulated Fatty Acid Uptake Plays a Causal Role in Hepatic Steatosis in Mice With Intact Leptin Signaling, But Not in ob/ob or db/db Mice.

[Abstract]Hepatic steatosis results from several processes. To assess their relative roles, hepatocellular long chain fatty acid (LCFA) uptake was assayed in hepatocytes from C57BL/6J control mice (C), mice with steatosis from a high fat diet (HFD) or 10, 14, or 18% ethanol (EtOH) in drinking water (functioning leptin signaling groups, FLSGs), and ob/ob and db/db mice. Uptake V(max) was increased vs C (p<0.001) and correlated significantly with liver weight and triglycerides in all FLSGs, but was minimally or not increased in ob/ob and db/db, in which liver weights & triglycerides greatly exceeded projections from regressions in FLSGs. Coefficients of determination (R(2)) for these FLSG regressions suggest that increased LCFA uptake accounts for ~80% of the increase in hepatic triglycerides within these groups, but increased lipogenic gene expression data suggest that enhanced LCFA synthesis is the major contributor in ob/ob and db/db. Got2, Cd36, Slc27a2, and Slc27a5 gene expression ratios were significantly up-regulated in the EtOH groups, correlating with both SREBP1c and V(max), but only Cd36 expression was increased in HFD, ob/ob, and db/db. Comparison of Vmax with serum insulin and leptin suggests that both hormones contribute to up-regulation of uptake in FLSG mice. Thus, increased LCFA uptake, reflecting SREBP1c-mediated up-regulation of 4 distinct transporters, is the dominant cause of steatosis in EtOH-fed mice. In ob/ob and db/db mice, increased LCFA synthesis appears more important. In FLSG animals insulin up-regulates hepatocellular LCFA uptake. Leptin appears either to up-regulate LCFA uptake or to be essential for full expression of up-regulation by insulin.

13: The Journal of clinical investigation, 2010 Aug 2, 120(8)
Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels.

[Abstract]Distinct populations of leptin-sensing neurons in the hypothalamus, midbrain, and brainstem contribute to the regulation of energy homeostasis. To assess the requirement for leptin signaling in the hypothalamus, we crossed mice with a floxed leptin receptor allele (Leprfl) to mice transgenic for Nkx2.1-Cre, which drives Cre expression in the hypothalamus and not in more caudal brain regions, generating LeprNkx2.1KO mice. From weaning, LeprNkx2.1KO mice exhibited phenotypes similar to those observed in mice with global loss of leptin signaling (Leprdb/db mice), including increased weight gain and adiposity, hyperphagia, cold intolerance, and insulin resistance. However, after 8 weeks of age, LeprNkx2.1KO mice maintained stable adiposity levels, whereas the body fat percentage of Leprdb/db animals continued to escalate. The divergence in the adiposity phenotypes of Leprdb/db and LeprNkx2.1KO mice with age was concomitant with increased rates of linear growth and energy expenditure in LeprNkx2.1KO mice. These data suggest that remaining leptin signals in LeprNkx2.1KO mice mediate physiological adaptations that prevent the escalation of the adiposity phenotype in adult mice. The persistence of severe adiposity in LeprNkx2.1KO mice, however, suggests that compensatory actions of circuits regulating growth and energy expenditure are not sufficient to reverse obesity established at an early age.

14: Diabetes, obesity & metabolism, 2010 Jul, 12(7)
Decrease in hepatic very-low-density lipoprotein-triglyceride secretion after weight loss is inversely associated with changes in circulating leptin.

[Abstract]Aim: Although weight loss usually decreases very-low-density lipoprotein-triglyceride (VLDL-TG) secretion rate, the change in VLDL-TG kinetics is not directly related to the change in body weight. Circulating leptin also declines with weight loss and can affect hepatic lipid metabolism. The aim of this study was to determine whether circulating leptin is associated with weight loss-induced changes in VLDL-TG secretion. Methods: Ten extremely obese subjects were studied. VLDL-TG secretion rate and the contribution of systemic (derived from lipolysis of subcutaneous adipose tissue TG) and non-systemic fatty acids (derived primarily from lipolysis of intrahepatic and intraperitoneal TG, and de novo lipogenesis) to VLDL-TG production were determined by using stable isotopically labelled tracer methods before and 1 year after gastric bypass surgery. Results: Subjects lost 33 +/- 12% of body weight, and VLDL-TG secretion rate decreased by 46 +/- 23% (p = 0.001), primarily because of a decrease in the secretion of VLDL-TG from non-systemic fatty acids (p = 0.002). Changes in VLDL-TG secretion rates were not significantly related to reductions in body weight, body mass index, plasma palmitate flux, free fatty acid or insulin concentrations. The change in VLDL-TG secretion was inversely correlated with the change in plasma leptin concentration (r = -0.72, p = 0.013), because of a negative association between changes in leptin and VLDL-TG secretion from non-systemic fatty acids (r = -0.95, p < 0.001). Conclusions: Weight loss-induced changes in plasma leptin concentration are inversely associated with changes in VLDL-TG secretion rate. Additional studies are needed to determine whether the correlation between circulating leptin and VLDL-TG secretion represents a cause-and-effect relationship.

15: FEBS letters, 2010 Jul 16, 584(14)
Modulation of hypothalamic PTP1B in the TNF-alpha-induced insulin and leptin resistance.

[Abstract]We have associated functional and molecular studies of insulin and leptin to investigate the effect of TNF-alpha on central insulin and leptin signaling in rats pre-treated with PTP1B-ASO. The icv infusion of TNF-alpha-induced an increase in PTP1B protein expression and activity, and attenuated insulin and leptin sensitivity and signaling in the hypothalamus. However, TNF-alpha was able to completely blunt the leptin and insulin effect in rats treated with PTP1B-ASO, suggesting that TNF-alpha does not require PTP1B to fully attenuate the leptin and insulin effects. In addition, our data also show that other mechanisms of insulin and leptin resistance are activated in the hypothalamus by TNF-alpha.

16: The Journal of clinical endocrinology and metabolism, 2010 Jun 9, 12(3)
Investigations of Thyroid Hormones and Antibodies in Obesity: Leptin Levels Are Associated with Thyroid Autoimmunity Independent of Bioanthropometric, Hormonal, and Weight-Related Determinants.

[Abstract]Objectives: Obesity can alter the thyroid hormone status as a result of a dysregulated endocrine loop between the hypothalamo-pituitary unit and adipose tissue. The adipocytokine leptin has been shown to promote autoimmunity; hence, we aimed to clarify whether leptin excess of obesity could increase the susceptibility to develop autoimmune thyroid disease (AITD). Study design: This cross-sectional study was performed in a tertiary care center. Methods: Free thyroid hormones, TSH, thyroglobulin, and antithyroid antibodies levels were tested in 165 obese and 118 lean subjects. Results were plotted against variables related to body composition, leptin levels, glucose homeostasis, energy expenditure, and pattern of weight accrual. Results: Compared with controls, obese patients had lower free T3 levels and free T4 levels (P < 0.01), greater prevalence of hypothyroidism (P < 0.05), and higher commonness of antithyroid antibodies (P < 0.05). As a marker of AITD, thyroid peroxidase antibodies were more frequent in the obese group (P < 0.01). Correlation analysis showed that leptin levels were associated with AITD (P < 0.01) independent of bioanthropometric variables. Multiple logistic regression analysis in pooled groups identified female sex and leptin as significant predictors of AITD. Conclusions: Obesity increases the susceptibility to harbor AITD with an emerging role for leptin as a peripheral determinant, which needs to be confirmed in future investigations.

17: Endocrinology, 2010 Jun 9, 12(3)
EGR1 Is a Target for Cooperative Interactions between Cholecystokinin and Leptin, and Inhibition by Ghrelin, in Vagal Afferent Neurons.

[Abstract]Food intake is regulated by signals from peripheral organs, but the way these are integrated remains uncertain. Cholecystokinin (CCK) from the intestine and leptin from adipocytes interact to inhibit food intake. Our aim was to examine the hypothesis that these interactions occur at the level of vagal afferent neurons via control of the immediate early gene EGR1. We now report that CCK stimulates redistribution to the nucleus of early growth response factor-1 (EGR1) in these neurons in vivo and in culture, and these effects are not dependent on EGR1 synthesis. Leptin stimulates EGR1 expression; leptin alone does not stimulate nuclear translocation, but it strongly potentiates the action of CCK. Ghrelin inhibits CCK-stimulated nuclear translocation of EGR1 and leptin-stimulated EGR1 expression. Expression of the gene encoding the satiety peptide cocaine- and amphetamine-regulated transcript (CARTp) is stimulated by CCK via an EGR1-dependent mechanism, and this is strongly potentiated by leptin. Leptin potentiated inhibition of food intake by endogenous CCK in the rat in conditions reflecting changes in EGR1 activation. The data indicate that by separately regulating EGR1 activation and synthesis, CCK and leptin interact cooperatively to define the capacity for satiety signaling by vagal afferent neurons; manipulation of these interactions may be therapeutically beneficial.

18: Arthritis research & therapy, 2010 Jun 9, 12(3)
Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis.

[Abstract]ABSTRACT: INTRODUCTION: Increasing evidence support the regulatory role of leptin in osteoarthritis (OA). As high circulating concentrations of leptin disrupt the physiological function of the adipokine in obese individuals, the current study has been undertaken to determine whether the elevated levels of leptin found in the joint from obese OA patients also induce changes in the chondrocyte response to leptin. METHODS: Chondrocytes isolated from OA patients with various body mass index (BMI) were treated with 20, 100 or 500 ng/ml of leptin. The expression of cartilage-specific components (aggrecan, type 2 collagen), as well as regulatory (IGF-1, TGFbeta, MMP-13, TIMP 2) or inflammatory (COX-2, iNOS, IL-1) factors was investigated by real-time PCR to evaluate chondrocyte responsiveness to leptin. Furthermore, the effect of body mass index (BMI) on leptin signalling pathways was analyzed with an enzyme-linked immunosorbent assay for STATs activation. RESULTS: Leptin at 20 ng/ml was unable to modulate gene expression in chondrocytes, except for MMP-13 in obese OA patients. Higher leptin levels induced the expression of IGF-1, type 2 collagen, TIMP-2 and MMP-13. However, the activity of the adipokine was shown to be critically dependent on both the concentration and the BMI of the patients with a negative association between the activation of regulated genes and BMI for 100 ng/ml of adipokine, but a positive association between chondrocyte responsiveness and BMI for the highest leptin dose. In addition, the gene encoding MMP-13 was identified as a target of leptin for chondrocytes originated from obese patients while mRNA level of TIMP-2 was increased in leptin-treated chondrocytes collected from normal or overweight patients. The adipokine at 500 ng/ml triggered signal transduction through a STAT-dependent pathway while 100 ng/ml of leptin failed to activate STAT 3 but induced STAT 1alpha phosphorylation in chondrocytes obtained from obese patients. CONCLUSIONS: The current study clearly showed that characteristics of OA patients and more expecially obesity may affect the responsiveness of cultured chondrocytes to leptin. In addition, the BMI-dependent effect of leptin for the expression of TIMP-2 and MMP-13 may explain why obesity is associated with an increased risk for OA.

19: PloS one, 2010, 5(6)
Deletion of inducible nitric-oxide synthase in leptin-deficient mice improves brown adipose tissue function.

[Abstract]BACKGROUND: Leptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice. METHODS AND FINDINGS: Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p<0.05), decreased amounts of total fat pads (p<0.05), lower food efficiency rates (p<0.05) and higher rectal temperature (p<0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1alpha), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents. CONCLUSION: Ablation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement.

20: Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2010 Jun 8, 12(3)
Early menopause association with employment, smoking, divorced marital status and low leptin levels.

[Abstract]Aims. The aims of this study were (1) to investigate the determining risk factors related to early menopause and (2) to compare the relationships between demographic characteristics and hormonal status and leptin levels in subjects with early (no surgical) and natural menopause. Study design. The prospective study was conducted on 500 women with early and 2700 women with natural menopause. Detailed information was collected about their employment status, past and present smoking habits, coffee and alcohol use, educational level and other factors relevant to health. Thirty participants with early menopause and 30 participants with natural menopause were evaluated for hormone and leptin levels. Results. Employment status (OR: 1.94), current smoking (OR: 1.80) and divorced marital status (OR: 1.79) were found to be significant risk factors for early menopause. Mean levels of leptin in natural and early menopause were measured 11.40 +/- 4.1 ng/ml and 8.01 +/- 3.9 ng/ml, respectively (p = 0001). Leptin levels in the early (r = 0.765, p = 0.001) and natural (r = 0.750, p = 0.001) menopause subjects correlated positively with oestradiol (E2) levels. Conclusion. This study shows that early onset of menopause is correlated with smoking, employment status, divorced marital status and lower leptin levels.

21: Cancer research, 2010 Jul 1, 70(13)
Interaction between Adiponectin and Leptin Influences the Risk of Colorectal Adenoma.

[Abstract]Obesity has been associated with an increased risk of colorectal neoplasia, but the mechanisms of this potential association have not been elucidated. We hypothesized that the adipokines adiponectin, leptin, and tumor necrosis factor-alpha (TNF-alpha) may mediate an association between obesity and colorectal cancer. We measured plasma concentrations of total and high-molecular-weight (HMW) adiponectin, leptin, and TNF-alpha in healthy volunteer examinees who underwent total colonoscopy between February 2004 and February 2005, and conducted a case-control study consisting of 778 cases and 735 controls. An inverse association of total and HMW adiponectin was observed with colorectal adenoma (P trend < 0.001 and 0.03, respectively). Further, total adiponectin interacted with leptin, but not TNF-alpha, in relation to colorectal adenoma (P interaction = 0.007). An inverse association of total adiponectin with colorectal adenoma was apparent in the highest two tertiles of leptin, particularly the middle (P trend < 0.001), whereas a positive association of leptin was obvious in the lowest tertile of total adiponectin (P trend = 0.01) after adjusting for potential confounders and body mass index, which is a major determinant of insulin resistance. Adiponectin may exert an anticarcinogenic effect on the large intestine by interfering with leptin, whereas leptin could conversely exert a carcinogenic effect under conditions of a lower abundance of adiponectin. Our findings provide the first epidemiologic evidence for interactive effects of adiponectin and leptin in the early stage of colorectal tumorigenesis, distinct from their involvement in insulin resistance. Cancer Res; 70(13); 5430-7. (c)2010 AACR.

22: European journal of endocrinology / European Federation of Endocrine Societies, 2010 Aug, 163(2)
Prediabetes is not all about obesity: association between plasma leptin and prediabetes in lean rural Chinese adults.

[Abstract]Objective This study investigated the associations of plasma leptin levels with insulin resistance (IR) and prediabetes in relatively lean, rural Chinese men and women. Design and methods This study included 574 subjects aged 21-45 years from a community-based twin cohort. Plasma leptin concentrations were measured by sandwich immunoassays using flowmetric xMAP technology. Prediabetes was defined based on fasting plasma glucose and 75-g oral glucose tolerance test. Multivariate linear and logistic regression analyses were used to investigate gender-specific associations of leptin with IR measures and prediabetes, adjusting for intra-twin correlation, measures of adiposity, and other pertinent covariates. Results The body mass index is 22.3+/-2.7 kg/m(2) in men and 22.5+/-2.7 kg/m(2) in women. Leptin levels were positively associated with IR. Individuals with higher tertiles of leptin also had increased risk of prediabetes with odds ratios (OR) of 2.6 (95% confidence interval (CI): 1.4-5.1) and 4.3 (95% CI: 2.1-8.7) in men; OR of 1.1 (95% CI: 0.6-2.1) and 3.1 (95% CI 1.5-6.2) in women for second and third tertile respectively. These associations were attenuated after further adjusting for adiposity measurements only in men. The leptin-prediabetes associations disappeared after adjusting for the homeostatic model assessment of IR in both genders. Conclusion In this sample of relatively lean rural Chinese adults, plasma leptin levels were associated with IR and prediabetes in a dose-response fashion, which were not totally explained by adiposity. Our data emphasize that prediabetes is not all about obesity, and leptin may be an additional biomarker for screening individuals at high risk for prediabetes in this population.

23: Endocrinology, 2010 Aug, 151(8)
Mammary ductal growth is impaired in mice lacking leptin-dependent signal transducer and activator of transcription 3 signaling.

[Abstract]Mice lacking leptin (ob/ob) or its full-length receptor (db/db) are obese and reproductively incompetent. Fertility, pregnancy, and lactation are restored, respectively, in ob/ob mice treated with leptin through mating, d 6.5 post coitum, and pregnancy. Therefore, leptin signaling is needed for lactation, but the timing of its action and the affected mammary process remain unknown. To address this issue, we used s/s mice lacking only leptin-dependent signal transducer and activator of transcription (STAT)3 signaling. These mice share many features with db/db mice, including obesity, but differ by retaining sufficient activity of the hypothalamic-pituitary-ovarian axis to support reproduction. The s/s mammary epithelium was normal at 3 wk of age but failed to expand through the mammary fat pad (MFP) during the subsequent pubertal period. Ductal growth failure was not corrected by estrogen therapy and did not relate to inadequate IGF-I production by the MFP or to the need for epithelial or stromal leptin-STAT3 signaling. Ductal growth failure coincided with adipocyte hypertrophy and increased MFP production of leptin, TNFalpha, and IL6. These cytokines, however, were unable to inhibit the proliferation of a collection of mouse mammary epithelial cell lines. In conclusion, the very first step of postnatal mammary development fails in s/s mice despite sufficient estrogen IGF-I and an hypothalamic-pituitary-ovarian axis capable of supporting reproduction. This failure is not caused by mammary loss of leptin-dependent STAT3 signaling or by the development of inflammation. These data imply the existence of an unknown mechanism whereby leptin-dependent STAT3 signaling and obesity alter mammary ductal development.

24: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 15, 184(12)
Leptin modulates innate and adaptive immune cell recruitment after cigarette smoke exposure in mice.

[Abstract]Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p<0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p<0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.

25: Clinica chimica acta; international journal of clinical chemistry, 2010 Sep 6, 411(17-18)
The relationship between the levels of gonadotropic hormones and OPG, leptin, TGF-beta1 and TGF-beta2 in Chinese adult women.

[Abstract]BACKGROUND: The relationship between the levels of gonadotropic hormones and bone metabolism-related cytokines in Chinese women is unclear. We investigated the relationship between FSH and LH and OPG, leptin, TGF-beta1, and TGF-beta2 in Chinese women. METHODS: A cross-sectional study of 694 Chinese women, aged 20 to 82y was conducted. Levels of serum FSH, LH, OPG, leptin, TGF-beta1, and TGF-beta2 were determined. RESULTS: In premenopausal females, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels seemly showed no correlation with the cytokine levels. In perimenopausal females, serum FSH and LH levels showed significant positive correlation with osteoprotegerin (OPG) and transforming growth factor-beta2 (TGF-beta2) levels (r=0.286 to 0.405, all P=0.000), whereas they showed negative correlation with TGF-beta1 levels (r=-0.413 and -0.354, all P=0.000). In postmenopausal females, FSH and LH levels showed positive correlation with OPG levels (r=0.247 and 0.241, all P=0.000), negative correlation with leptin and TGF-beta1 levels (r=-0.234 to -0.319, all P=0.000), and no correlation with TGF-beta2 levels. Multiple linear regression stepwise analysis revealed the following results. In premenopausal females, 2.0% and 1.5% of the changes in LH could be explained by OPG and leptin, respectively, while 1.9% of the changes in OPG could be explained by LH. In perimenopausal females, the determinants of OPG and TGF-beta1 on FSH were 10.9% and 17.0%, respectively, and the determinants of OPG, TGF-beta1 and TGF-beta2 on LH were 4.5%, 4.9% and 16.4%, respectively. The determinants of FSH and LH on OPG were 14.5% and 2.5%, respectively. The determinant of FSH on TGF-beta1 was 4.5%, while the determinant of LH on TGF-beta2 was 16.4%. In postmenopausal females, the determinants of leptin and OPG on FSH were 10.2% and 2.8%, respectively, and the determinants of OPG and TGF-beta1 on LH were 5.8% and 2.3%, respectively. The determinant of FSH on OPG, leptin and TGF-beta1 were 6.1%, 3.4% and 9.2%. CONCLUSIONS: These results indicate that age-related gonadotropic hormone levels are associated with changes in OPG, TGF-beta1, TGF-beta2 and leptin, and change with menopausal status.

26: Behavioural brain research, 2010 Dec 1, 213(2)
The different satiating capacity of CHO and fats can be mediated by different effects on leptin and ghrelin systems.

[Abstract]Leptin and ghrelin are known to be the main hormones involved in the control of food intake, with opposite effects. Here we aimed to assess whether changes in leptin and ghrelin systems can be involved in the different satiating capacities of carbohydrates (CHO) and fat. Adult male Wistar rats were studied under 24h fasting conditions and after 24h fasting followed by a 12h re-feeding period with 64 kcal of CHO or fat, consisting of a mixture of wheat starch and sucrose or bacon, respectively. Serum levels of leptin and ghrelin, and mRNA levels of leptin and ObRb in the retroperitoneal and inguinal adipose tissue and of NPY, POMC, ObRb and GSHR in the hypothalamus were measured. CHO re-feeding resulted in higher leptin mRNA expression levels in the retroperitoneal adipose tissue and in higher circulating leptin levels compared with those after fat re-feeding. Moreover, circulating ghrelin levels and ghrelin/leptin ratio were significantly higher after fat re-feeding compared with CHO re-feeding, and hypothalamic expression levels of ghrelin receptor increased after fat, but not after CHO, re-feeding. Hence, expression levels of hypothalamic neuropeptides involved in food intake control and regulated by these hormones, particularly the orexigenic NPY and the anorexigenic pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone, were also differently affected by CHO and fat re-feeding, resulting in a significantly lower NPY/POMC ratio after CHO re-feeding than after fat re-feeding. In conclusion, different effects on the leptin and ghrelin systems can account, at least in part, for the lower satiating capacity of fat compared to CHO.

27: Eating behaviors, 2010 Aug, 11(3)
Circulating leptin moderates the effect of stress on snack intake independent of body mass.

[Abstract]Prior studies have demonstrated influences of leptin on hunger and satiety, the processing of food reward, and taste and palatability perception. This pilot study tested whether leptin accounts for variability in stress-induced changes in snack intake, and explored potential mechanisms underlying this effect. Thirty-four normal weight and class I obese women were exposed to a 30-minute mental stressor and a non-stressful control task in counterbalanced order on consecutive days. Higher serum leptin concentrations predicted decreases in snack intake following the stressor relative to the control condition. Leptin was not a significant predictor of overall hunger or stress-induced changes in hunger, but was associated with greater perceived palatability of one of the four snacks. Overall, findings suggest that leptin may moderate the effect of stress on energy intake through non-homeostatic mechanisms.

28: Regulatory peptides, 2010 Aug 9, 163(1-3)
Osteogenic differentiation of bone marrow mesenchymal stem cells by adenovirus-mediated expression of leptin.

[Abstract]Previous studies demonstrate that leptin has an osteogenic differentiation effect on bone marrow mesenchymal stem cells (MSCs). However, the effect of adenovirus-mediated leptin on MSCs differentiation has not been reported. To explore the mechanism, we constructed a recombinant adenoviral vector Ad-leptin and transfected propagated MSCs in vitro. The effects of Ad-leptin on MSCs growth and osteogenic differentiation were examined. The results showed that Ad-leptin inhibited the transfected MSCs growth significantly, and up-regulated osteocalcin expression and alkaline phosphatase activity. The expression of Cbfalpha1 and Cbfbeta which were the key factors in osteogenic differentiation was also up-regulated. All the findings suggest that genetic engineering of MSCs to express leptin gene may have potential application in the treatment of several genetic diseases and bone reconstruction.

29: Journal of lipid research, 2010 Aug, 51(8)
Absence of adipose differentiation related protein upregulates hepatic VLDL secretion, relieves hepatosteatosis, and improves whole body insulin resistance in leptin-deficient mice.

[Abstract]We previously showed that adipose differentiation related protein (Adfp)-deficient mice display a 60% reduction in hepatic triglyceride (TG) content. In this study, we investigated the role of ADFP in lipid and glucose homeostasis in a genetic obesity model, Lep(ob/ob) mice. We bred Adfp(-/-) mice with Lep(ob/ob) mice to create Lep(ob/ob)/Adfp(-/-) and Lep(ob/ob)/Adfp(+/+) mice and analyzed the hepatic lipids, lipid droplet (LD) morphology, LD protein composition and distribution, lipogenic gene expression, and VLDL secretion, as well as insulin sensitivity of the two groups of mice. Compared with Lep(ob/ob)/Adfp(+/+) mice, Lep(ob/ob)/Adfp(-/-) mice displayed an increased VLDL secretion rate, a 25% reduction in hepatic TG associated with improvement in fatty liver grossly and microscopically with a change of the size of LDs in a proportion of the hepatocytes and a redistribution of major LD-associated proteins from the cytoplasmic compartment to the LD surface. There was no detectable change in lipogenic gene expression. Lep(ob/ob)/Adfp(-/-) mice also had improved glucose tolerance and insulin sensitivity in both liver and muscle. The alteration of LD size in the liver of Lep(ob/ob)/Adfp(-/-) mice despite the relocation of other LDPs to the LD indicates a nonredundant role for ADFP in determining the size and distribution of hepatic LDs.

30: Diabetes, 2010 Jul, 59(7)
Leptin deficiency causes insulin resistance induced by uncontrolled diabetes.

[Abstract]OBJECTIVE: Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS: Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS: Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS: We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.

31: Diabetes, obesity & metabolism, 2010 May, 12(5)
Leptin-based glycopeptide induces weight loss and simultaneously restores fertility in animal models.

[Abstract]Aim: To design, manufacture and test a second generation leptin receptor (ObR) agonist glycopeptide derivative. The major drawback to current experimental therapies involving leptin protein is the appearance of treatment resistance. Our novel peptidomimetic was tested for efficacy and lack of resistance induction in rodent models of obesity and appetite reduction. Methods: The glycopeptide containing two additional non-proteinogenic amino acids was synthesized by standard solid-phase methods. Normal mice were fed with peanuts until their blood laboratory data and liver histology showed typical signs of obesity but not diabetes. The mice were treated with the peptidomimetic at 0.02, 0.1 or 0.5 mg/kg/day intraperitoneally side-by-side with 0.1 mg/kg/day leptin for 11 days. After termination of the assay, the blood cholesterol and glucose amounts were measured, the liver fat content was visualized and quantified and the remaining mice returned to normal diet and were allowed to mate. In parallel experiments normal rats were treated intranasally with the glycopeptide at 0.1 mg/kg/day for 10 days. Results: The 12-residue glycosylated leptin-based peptidomimetic E1/6-amino-hexanoic acid (Aca) was designed to target a principal leptin/ObR-binding interface. E1/Aca induced leptin effects in ObR-positive cell lines at picomolar concentrations and readily crossed the blood-brain barrier (BBB) following intraperitoneal administration. The peptide initiated typical leptin-dependent signal transduction pathways both in the presence and absence of leptin protein. The peptide also reduced weight gain in mice fed with high-fat peanut diet in a dose-dependent manner. Obese mice receiving peptide E1/Aca at a 0.5 mg/kg/day dose lost weight, corresponding to a net 6.5% total body weight loss, while similar mice treated with leptin protein did not. Upon cessation of the weight loss treatment, several obesity-related pathologies (i.e. abnormal metabolic profile and liver histology as well as infertility) normalized in peptide-, but not leptin-treated, mice. Peptide E1/Aca added intranasally to growing normal rats decelerated normal weight gain corresponding to a net 6.8% net total body weight loss with statistical significance. Conclusions: No resistance induction to peptide E1/Aca or toxicity in either obese or healthy rodents was observed, indicating the potential for widespread utility of the peptidomimetic in the treatment of leptin-deficiency disorders. We provide additional proof for the hypothesis that difficulties in current leptin therapies reside at the BBB penetration stage, and we document that by either glycosylation or intranasal peptide administration we can overcome this limitation.

32: Diabetes care, 2010 Jul, 33(7)
Ethnic Variation in Adiponectin and Leptin Levels and Their Association With Adiposity and Insulin Resistance.

[Abstract]OBJECTIVE To investigate ethnic differences in adiponectin and leptin concentration and to determine whether these adipokines and a high-glycemic index diet account for ethnic variation in insulin resistance. RESEARCH DESIGN AND METHODS In 1,176 South Asian, Chinese, Aboriginal, and European Canadians, fasting blood samples were drawn, and clinical history and dietary habits including glycemic index/glycemic load were recorded using standardized questionnaires. Insulin resistance was defined using homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS Adiponectin concentrations were significantly higher in Europeans (adjusted mean 12.94 [95% CI 2.27-13.64]) and Aboriginal people (11.87 [11.19-12.59]) than in South Asians (9.35 [8.82-9.92]) and Chinese (8.52 [8.03-9.03]) (overall P < 0.001). Serum leptin was significantly higher in South Asians (11.82 [10.72-13.04]) and Aboriginal people (11.13 [10.13-12.23]) than in Europeans (9.21 [8.38-10.12]) and Chinese (8.25 [7.48-9.10]). BMI and waist circumference were inversely associated with adiponectin in every group except the South Asians (P < 0.001 for interaction). Adiponectin was inversely and leptin was positively associated with HOMA-IR (P < 0.001). The increase in HOMA-IR for each given decrease in adiponectin was larger among South Asians (P = 0.01) and Aboriginal people (P < 0.001) than among Europeans. A high glycemic index was associated with a larger decrease in adiponectin among South Asians (P = 0.03) and Aboriginal people (P < 0.001) and a larger increase in HOMA-IR among South Asians (P < 0.05) relative to that in other groups. CONCLUSIONS South Asians have the least favorable adipokine profile and, like the Aboriginal people, display a greater increase in insulin resistance with decreasing levels of adiponectin. Differences in adipokines and responses to glycemic foods parallel the ethnic differences in insulin resistance.

33: Atherosclerosis, 2010 Aug, 211(2)
Carotid intima media thickness is associated with plasma adiponectin but not with the leptin:adiponectin ratio independently of metabolic syndrome.

[Abstract]PURPOSE: A recent report showed no benefit of the leptin:adiponectin ratio (L:A ratio) over individual adipokine levels in CHD prediction [8]. We determined associations of carotid intima media thickness (IMT) with the L:A ratio taking account of cardiovascular risk factors in a high risk population. METHODS: IMT, plasma leptin, adiponectin and the L:A ratio were determined in 161 middle-aged men and women (45% metabolic syndrome). RESULTS: IMT was associated inversely with adiponectin and positively with the L:A ratio in age- and sex-adjusted multiple linear regression analyses (P<0.001 for both). After controlling for metabolic syndrome, the independent association with adiponectin remained (P<0.001), but the relationship with the L:A ratio disappeared (P=0.126). Results were similar after additional adjustment for diabetes status or for insulin resistance. CONCLUSION: This study does not support the preferential use of the leptin:adiponectin ratio as a marker of atherosclerosis susceptibility.

34: The Journal of comparative neurology, 2010 Jun 1, 518(11)
Identifying the efferent projections of leptin-responsive neurons in the dorsomedial hypothalamus using a novel conditional tracing approach.

[Abstract]Tracing the axonal projections of selected neurons is labor intensive and inherently limited by currently available neuroanatomical methods. We developed an adeno-associated virus (AAV) that can be used for efficiently tracing identified neuronal populations. The virus encodes a humanized Renilla green fluorescent protein (hrGFP) that is transcriptionally silenced by a neo cassette flanked by LoxH/LoxP sites (AAV-lox-Stop-hrGFP). Thus, hrGFP is expressed only in neurons with Cre recombinase activity. To demonstrate the utility of this approach, the virus was injected unilaterally into the dorsomedial hypothalamus (DMH) of mice that express Cre in neurons expressing the leptin receptor. Animals with DMH injections showed robust hrGFP expression in DMH neurons, as visualized by its endogenous fluorescence or following immunolabeling. We found that hrGFP was expressed in approximately one-third to one-half of Cre-expressing neurons at the site of injection, but not in non-Cre-expressing neurons. The expression of GFP allowed us to identify the projection fields of DMH leptin-responsive neurons. Our results show hrGFP-positive axonal projections and terminals in the paraventricular nucleus of the hypothalamus, arcuate nucleus, preoptic area, bed nucleus of the stria terminalis, paraventricular thalamus, periaqueductal gray, and precoeruleus. The aforementioned pattern of projections was similar to DMH projections determined by injections of biotinylated dextran amine in the mouse DMH. Interestingly, some hrGFP-positive terminals were seen contacting the ependymal layer of the third and fourth ventricles. In summary, this approach is an effective tool for tracing axonal projections of chemically identified neurons, including leptin-responsive neurons.

35: European journal of endocrinology / European Federation of Endocrine Societies, 2010 Jul, 163(1)
Acute exogenous TSH administration stimulates leptin secretion in vivo.

[Abstract]TSH-receptor (TSHR) has been found in a variety of cell types, including preadipocytes and adipocytes. In vitro, TSH-mediated preadipocyte and adipocyte responses include proliferation, differentiation, survival, and lipolysis. Objective To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo. Patients One hundred patients with differentiated thyroid cancer already treated by total thyroidectomy and (131)I remnant ablation were enrolled. Mean (+/-s.e.m.) body mass index (BMI) was 26.9+/-0.6 kg/m(2). Methods Patients received a standard dose of rhTSH for measurement of thyroglobulin in the follow-up of their disease. Blood samples were taken for the assay of TSH and leptin before the first administration of rhTSH (time 0), and 24 h (time 1), 48 h (time 2), 72 h (time 3), and 96 h (time 4) after the first administration of rhTSH. Results Significant mean serum leptin increments, with respect to basal value, were 16, 13, 18, and 11% at times 1, 2, 3, and 4 respectively. Significant positive correlations of leptin-area under the curve with respect to basal leptin levels (r=0.43; P<0.0001) and BMI (r=0.32; P<0.005) were observed. Conclusions Acute rhTSH administration in hypothyroid subjects under l-thyroxine therapy produces a rise in serum leptin. This increase is proportional to the adipose mass suggesting that a functioning TSHR is expressed on the surface of adipocytes. The role that TSHR activation in adipocytes might play in physiological and pathological conditions remains a matter of investigation.

36: Biomaterials, 2010 Jul, 31(19)
A leptin derived 30-amino-acid peptide modified pegylated poly-L-lysine dendrigraft for brain targeted gene delivery.

[Abstract]The blood-brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone-leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-L-lysine (DGL) is used as non-viral gene vector in this study. DGL-PEG-Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL-PEG-Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL-PEG-Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood-brain barrier.

37: Journal of lipid research, 2010 Aug, 51(8)
Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice.

[Abstract]The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.

38: Steroids, 2010 Oct, 75(10)
Effect of serum estradiol and leptin levels on thyroid function, food intake and body weight gain in female Wistar rats.

[Abstract]We evaluated the interplay among estrogen, leptin and thyroid function in the regulation of body mass in female rats. Adult female rats were divided into four groups: control (C, sham-operated), ovariectomized (OVX), ovariectomized treated with estradiol benzoate (Eb) 0.7 or 14microg/100gbw per day, during 21 days. OVX led to an increase in body mass, food intake and food efficiency (change in body mass as function of the amount of food ingested) which were normalized by the lower Eb dose, and decreased significantly when the higher dose was given. Serum leptin levels were increased more than two-fold in all ovariectomized groups. Serum T4 levels of the Eb treated OVX were significantly lower than in the controls. Serum T3 and TSH were unaffected by OVX or by Eb treatment. Uterine type 2 iodothyronine deiodinase (D2) activity changed in parallel with serum estradiol: decreased after OVX, returned to control levels after the lower E2 treatment, and increased significantly after the high Eb dosage. The hypothalamic D2 activity was reduced around 30% in all castrated groups, treated or not with estrogen, whereas in the brown adipose tissue the enzyme was not changed. Interestingly, although estrogen-treated OVX rats had lower body weight, serum leptin was high, suggesting that estrogen increases leptin secretion. Our results show that estradiol is necessary for the hypothalamic action of leptin, since the increase in leptin levels observed in all ovariectomized rats was associated with a decrease in food intake and food efficiency only in the rats treated with estrogen.

39: American journal of physiology. Endocrinology and metabolism, 2010 May, 298(5)
Programming of rat adrenal medulla by neonatal hyperleptinemia: adrenal morphology, catecholamine secretion, and leptin signaling pathway.

[Abstract]Leptin serum concentration in early life is an important factor for adequate future development of the offspring. Previously, we demonstrated that hyperleptinemia on lactation programmed for hyperleptinemia, central leptin resistance with lower expression of the long form of leptin receptor at hypothalamus, and higher medullary catecholamine levels with cardiovascular consequences at adulthood. The central objective of this study was to determine the direct effect of leptin on adrenal medullary function of adult rats that were leptin treated during lactation. Adrenal morphology was also accessed. Recombinant murine leptin was injected in the pups during the first 10 days of life (group L, leptin-programmed) or at adulthood during 6 days (group LC). The controls of both experiments received saline (groups C and CC). Both treatments resulted in hyperleptinemia at 150 days old (+78% and 2-fold increase, respectively; P < 0.05). Programmed animals showed hypertrophy of adrenal and higher adrenal catecholamine content at 150 days old (3-fold increase, P < 0.05), and no changes were observed in the LC group. However, LC rats had lower adrenal content of tyrosine hydroxylase (-17%, P < 0.05). Leptin-programmed rats had a lower response to leptin in vitro stimulation (-22%, P < 0.05) and lower expression of key proteins of the leptin signaling pathway, leptin receptor and janus tyrosine kinase 2 in the medullas (-61% and -29%, respectively, P < 0.05). However, they presented higher expression of phosphorylated signal transducer and activator of transcription 3 (+2-fold, P < 0.05). Leptin treatment at adulthood did not affect these parameters. The higher catecholamine synthesis and secretion in the leptin-programmed rats observed in our previous study does not seem to be a consequence of the direct effect of leptin on the medullas. We suggest that the hyperleptinemia of the programmed animals increases adrenal medullary function through sympathetic nervous system activation. In conclusion, high leptin levels on lactation program the activity of the sympathoadrenal system at adulthood that may contribute to the development of adult chronic diseases such as hypertension.

40: Rheumatology international, 2010 Mar 18, 285(12)
Effects of Spa therapy on serum leptin and adiponectin levels in patients with knee osteoarthritis.

[Abstract]Adipocytokine, including leptin and adiponectin, may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether spa therapy modified plasma levels of leptin and adiponectin in thirty patients with knee OA treated with a cycle of a combination of daily locally applied mud-packs and bicarbonate-sulphate mineral bath water. Leptin and adiponectin plasma levels were assessed at baseline and after 2 weeks, upon completion of the spa treatment period. The concentrations of leptin and adiponectin were measured by ELISA. At basal time, plasma leptin levels were significantly correlated with body mass index (BMI) and gender, but no significant correlation was found with patient age, duration of disease, radiographic severity of knee OA, VAS score or Lequesne index. There was no correlation between plasma adiponectin level and BMI, gender and age, duration of the disease, radiographic severity of knee OA and VAS score. A significant correlation of plasma adiponectin levels was found only with the Lequesne index. At the end of the mud-bath therapy cycle, serum leptin levels showed a slight but not significant increase, while a significant decrease (P < 0.05) in serum adiponectin levels was found. However, leptin and adiponectin concentrations after treatment were not correlated with other clinical parameters. In conclusion, our data show that spa therapy can modify plasma levels of the adipocytokines leptin and adiponectin, important mediators of cartilage metabolism. Whether this effect may play a potential role in OA needs further investigations.

41: Biology of reproduction, 2010 Mar 17, 285(12)
17Beta-Estradiol Enhances Leptin Expression in Human Placental Cells Through Genomic and Nongenomic Actions.

[Abstract]The process of embryo implantation and trophoblast invasion is considered the most limiting factor for the establishment of pregnancy. Leptin was originally described as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in the placenta, where it was found to be expressed. In the present work, we have found a stimulatory effect of 17beta-estradiol (E(2)) on endogenous leptin expression, as analyzed by Western blot, in both BeWo choriocarcinoma cell line and normal placental explants. This effect was time and dose dependent. Maximal effect was achieved at 10 nM in BeWo cells and 1 nM in placental explants. Estradiol effect involved the estrogen receptor as the antagonist ICI 182,780 inhibited E(2) induced leptin expression. Moreover, E(2) treatment enhanced leptin promoter activity up to 4 times, evaluated by transient transfection with a plasmid construction containing the leptin promoter region and the reporter gene luciferase. This effect was dose dependent. Deletion analysis demonstrated that a minimal promoter region between -1951 and -1847 bp is both necessary and sufficient to evidence E(2) effect. Estradiol action involved estrogen receptor 1, previously known as estrogen receptor alpha, as cotransfection with a vector encoding estrogen receptor 1 potentiated E(2) effect on leptin expression. Moreover, E(2) action probably involves membrane receptors too, as treatment with estradiol-BSA complex partially enhanced leptin expression. Estradiol effect could be blocked by pharmacologic inhibition of MAPK and the phosphoinositide-3-kinase (PI3K) pathways with 50 microM PD98059 and 0.1 microM Wortmannin respectively. Moreover, cotransfection of dominant negative mutants of MAP2K or MAPK blocked E(2) induction on leptin promoter. On the other hand, E(2) treatment promoted MAPK1/MAPK3 and AKT phosphorylation in placental cells. In conclusion, we provide evidence suggesting that E(2) induces leptin expression in trophoblastic cells, probably through genomic and nongenomic actions via crosstalk between estrogen receptor 1 and MAPK and PI3K signal transduction pathways.

42: European journal of endocrinology / European Federation of Endocrine Societies, 2010 Mar 17, 285(12)
Resistance to leptin replacement therapy in Berardinelli-Seip congenital lipodystrophy (BSCL): An immunological origin.

[Abstract]Context: In a 4-month proof-of-concept trial, beneficial metabolic effects were recently reported in non-diabetic children with BSCL; this information prompted us to hypothesize that long-term leptin replacement therapy might improve or reverse the early complications of the disease in these patients. Patients and methods: A 28-month trial was implemented in 8 patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding-assay and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (NMDA) and the patient serum, with or without leptin. Results: A negative or partial response to treatment was observed in 5 of 8 patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders and paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from 2 patients with a negative response inhibited the neuroprotective effect of leptin. Conclusion: Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

43: Life sciences, 2010 Apr 24, 86(17-18)
Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectin.

[Abstract]AIMS: Our aim was to evaluate the effect of exercise training (TR) on adipocyte-size-dependent expression of leptin and adiponectin. MAIN METHODS: Male Wistar rats were divided into 2 groups, sedentary control (CR) and TR group, and both monitored for 9weeks. Adipocytes isolated from epididymal, retroperitoneal, and inguinal fat depots were independently separated into 3 fractions of different cell size, and the relationships between adipocyte size and either leptin or adiponectin mRNA were determined by real-time RT-PCR analysis. KEY FINDINGS: In epididymal and inguinal adipose tissue, positive relationships between adipocyte size and both leptin and adiponectin mRNA expression were found. Comparison of TR and CR rats showed no significant effect of TR on the slopes of the linear regression lines of correlation between leptin mRNA and adipocyte size in either adipose tissue, whereas the slopes of the regression line of correlation between adipocyte size and adiponectin mRNA were greater in TR group. Leptin levels per milliliter of plasma were significantly lower in TR than CR rats, whereas leptin levels adjusted to the 3 fat depots did not differ. TR did not affect adiponectin levels in plasma, whereas adiponectin levels adjusted to the 3 fat depots were significantly greater in TR than CR group. SIGNIFICANCE: TR-induced reduction in leptin mRNA expression was closely associated with smaller adipocyte size. However, TR amplified the adipocyte-size-dependent expression of adiponectin mRNA, suggesting that TR-induced alterations in adiponectin mRNA may also be mediated by factor(s) other than adipocyte size.

44: Hypertension, 2010 Apr, 55(4)
Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.

[Abstract]The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 mug) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals.

45: Hypertension, 2010 Apr, 55(4)
Obesity, sympathetic overdrive, and hypertension: the leptin connection.

[Abstract]The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 mug) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals.

46: Clinica chimica acta; international journal of clinical chemistry, 2010 May 2, 411(9-10)
Relationships between serum adiponectin, leptin concentrations and bone mineral density, and bone biochemical markers in Chinese women.

[Abstract]BACKGROUND: Adiponectin and leptin, as the main circulating peptides secreted by adipose tissue, are potential contributors to bone metabolism. However, their association with bone mineral density (BMD) is unknown. We investigated whether these serum adipocytokines concentrations are associated with BMD and bone turnover markers. METHODS: Serum adiponectin, leptin concentrations, bone turnover biochemical markers, and BMD were determined in 265 premenopausal and 336 postmenopausal Chinese women. RESULTS: In postmenopausal Chinese women, the multiple linear stepwise regression analysis showed that year since menopause, lean mass, estradiol, and adiponectin, but not fat mass, leptin, were independent predictors of BMD in postmenopausal Chinese women. However, in premenopausal Chinese women, adiponectin was not the predictor of BMD. The significant positive correlations between adiponectin and bone-specific alkaline phosphatase (BAP), bone cross-linked N-telopeptides of type I collagen (NTX) were found only in postmenopausal women. Serum BAP, and NTX, but not adiponectin, decreased in response to alendronate therapy. CONCLUSIONS: Adiponectin was an independent predictor of BMD, and positively correlated with bone turnover biochemical markers in postmenopausal Chinese women, but not premenopausal women. It suggested that adiponectin may exert a negative effect on bone mass by promoting excessive bone resorption associated with bone loss. However, these effects may be mediated by menopausal status.

47: The Journal of dairy research, 2010 May, 77(2)
Expression and function of leptin and its receptor in dairy goat mammary gland.

[Abstract]Leptin is an autocrine and paracrine factor which affects the development and function of mammary gland. The purpose of this study was to investigate the presence and regulatory effect of leptin in Chinese Guan Zhong dairy goat mammary gland from the virgin state to involution. The protein expression and localization of leptin and its long form receptor (OB-Rb) were detected by western blot and a confocal laser scanning microscope. Explants were cultured to detect the impacts of leptin on mammary gland, western blot was used to research leptin signal transduction pathway in pregnancy, lactation and involution. Leptin and amounts of OB-Rb protein were high throughout the virgin stage and at the beginning of pregnancy, lower at mid-pregnancy and throughout lactation, then higher at involution. Immunofluorescence performed with the anti-leptin and anti-leptin receptor antibody showed labelling located in adipose, epithelial cells, or extracellular matrix at different stages. The localization of leptin and OB-Rb revealed that leptin induced the expression of OB-Rb specifically and controlled the development and physiological function of the mammary gland by binding to OB-Rb. Leptin stimulated the proliferation and differentiation of ductal epithelial cells in pregnancy by JAK-MAPK signal pathway, enhanced the amount of beta-casein in cultured lactating mammary gland by JAK-STAT5 signal pathway, made the mammary duct disappear and induced apoptosis of mammary epithelial cells and mammary gland restitution by JAK-STAT3 signal pathway in involution. Overall, this study demonstrated the importance and complexity of leptin and OB-Rb during mammary gland development and provides a valuable resource for future research in this area.

48: Physiological genomics, 2010 Feb 16, 31(1)
Genes unlinked to the leptin receptor influence urinary albumin excretion in obese Zucker rats.

[Abstract]We have previously shown that 90% of outbred obese Zucker Lepr(fa/fa) rats die prematurely of renal disease. Thus, renal disease in obese Zucker Lepr(fa/fa) rats may be caused by the LEPR mutation on chromosome 5, by the obesity, or it may be influenced by Zucker susceptibility alleles of genes on other chromosomes. We have searched for susceptibility genes on other chromosomes using urinary albumin excretion (UAE) as an early indicator of altered renal function in a backcross of (Brown Norway x inbred Zucker) F1 x inbred Zucker, which we name the BZZ cross. 237 BZZ backcross animals were sacrificed at 15 weeks of age. All included animals were homozygous for the fatty mutation of LEPR and were obese. Urinary creatinine measurements were used to calculate the Albumin to Creatinine Ratio (ACR). We identified direct effect quantitative trait loci (QTLs) for UAE and ACR on Chromosome 1 (LOD scores = 3.6 and 2.86, respectively) in males, and Chromosome 4 (LOD score = 2.9) in females. Significant QTLs were identified for left kidney weight for females on Chromosomes 3 and 12. We also demonstrated that kidneys from 15 week old obese inbred Zucker rats already show evidence of kidney pathology: tubular dilation, proteinaceous fluid accumulation, evidence for inflammation, and mild mesangial and tubular membrane basement membrane thickening. Both lean Zucker rats and the BN rats showed no evidence for these changes. Thus, by removing the influence of the Lepr(fa/fa) mutation from analysis we have identified UAE QTLs unlinked to LEPR. Key words: urinary albumin excretion, Zucker, kidney, UAE.

49: Molecular biology reports, 2010 Feb 12, 518(4)
Leucine promotes leptin receptor expression in mouse C2C12 myotubes through the mTOR pathway.

[Abstract]Leptin plays a critical role in regulating muscle protein metabolism by binding with leptin receptors in a 1:1 stoichiometry. However, the role for leucine in the regulation of leptin receptor expression in muscle has not been investigated. The present study was conducted to test the hypothesis that leucine regulates leptin receptor levels in C2C12 myotubes. Cells were cultured in the presence of DMEM/F12 medium containing supplemental 0 or 5 mM L: -leucine. Leptin receptor expression by C2C12 myotubes peaked at 2 h post-supplementation. Additionally, leucine stimulated leptin receptor expression at both mRNA and protein levels in a dose-dependent manner. Furthermore, leucine enhanced the phosphorylation of mammalian target of rapamycin (mTOR). Addition of rapamycin (an inhibitor of mTOR) to culture medium completely suppressed leucine-induced activation of mTOR and inhibited leucine-stimulated leptin receptor production. These results indicate that leucine affects leptin receptor expression in muscle cells via the mTOR signaling pathway.

50: American journal of hypertension, 2010 Feb 11, 518(4)
Influence of Leptin, Adiponectin, and Resistin on the Association Between Abdominal Adiposity and Arterial Stiffness.

[Abstract]BackgroundAdiposity is associated with arterial stiffness, and both adiposity and arterial stiffness independently predict morbidity and mortality. Because adipocytes account for most adipokine production, the objectives of this study were to examine the influence of adipokines such as leptin, adiponectin, and resistin on the relationship between abdominal adiposity and arterial stiffness.MethodsThis is a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). Adiposity was measured as kilograms of abdominal adipose tissue using dual-energy X-ray absorptiometry (DXA). Arterial stiffness was assessed as carotid-femoral pulse wave velocity (PWV). Leptin, adiponectin, and resistin were assayed in fasting serum samples. The influence of adipokines on the relationship between adiposity and arterial stiffness by adipokines was examined using standard mediation pathway analysis.ResultsAmong 749 participants ages 26-96 years (mean age 67, 52% men, 27% black), abdominal adiposity was positively associated with PWV (relative ratio (RR) = 1.04, P = 0.02), after adjusting for potential confounders but was attenuated and no longer significant after adjusting for leptin (RR = 0.99, P = 0.77). The relationship between adiposity and PWV was not substantially influenced by adiponectin (RR = 1.03, P = 0.06) or resistin (RR = 1.05, P = 0.010). Leptin (RR = 1.02, P < 0.001), resistin (RR = 0.92, P < 0.0001), and adiponectin (RR = 0.97, P = 0.004), but not abdominal adiposity (RR = 1.00, P = 0.94), retained significant associations with PWV when adjusting for each other and confounders.ConclusionsOur findings are consistent with the hypothesis that leptin explains, in part, the observed relationship between abdominal adiposity and arterial stiffness. Adiponectin, leptin, and resistin are independent correlates of PWV.American Journal of Hypertension (2010). doi:10.1038/ajh.2010.8.

51: Neuro endocrinology letters, 2010 Feb 11, 31(1)
Serum leptin is correlated to high turnover in osteoporosis.

[Abstract]OBJECTIVE: Clinical data have suggested that obesity protects against osteoporosis. Leptin, mainly secreted by white adipose tissue, might be involved by mediating an effect on bone metabolism. This study was conducted to investigate a possible relationship of leptin and bone turn-over in postmenopausal women with osteoporosis. METHODS: We measured bone mineral density (BMD), serum leptin levels and markers of bone metabolism, including osteocalcin and cross-laps in 44 patients with osteoporosis. The main group consisted of 32 postmenopausal women. RESULTS: Mean serum leptin was 13.1 microg/L and showed no statistically significant difference to the levels measured in a collective of normal persons adjusted for age and BMI. When related to serum cross-laps as markers of bone resorption, a positive correlation (p<.05) was observed, whereas no correlation with osteocalcin could be seen. CONCLUSION: A dual control of bone formation by leptin is assumed: This involves local mechanisms acting on osteoblasts and a central inhibitory effect on bone metabolism via a hypothalamic relay. Our data indicate that the net effect of circulating leptin may cause bone loss and is significantly related to high-turnover serum bone markers, at least in postmenopausal women with osteoporosis.

52: Clinical endocrinology, 2010 Feb 10, 31(1)
Does leptin predict incident hypertension in older adults?

[Abstract]Summary Objective: Leptin is associated with blood pressure (BP) in experimental and cross-sectional studies, but only one previous prospective study of middle-aged men has reported the association between leptin and incident hypertension. We examined the association of leptin levels with incident hypertension in a population-based study of older men and women. Design: Longitudinal cohort study Population: Participants were 602 community-dwelling older adults with normal baseline BP levels who attended a research clinic visit between 1984 and 1987 and again 4.4 years later (mean age was 66.2+/-11.4; 60.6% were men; mean BMI 24.9+/-3.4 kg/m(2)). Measurements: Hypertension was defined as systolic BP >/=140 mmHg and/or diastolic BP >/=90 mmHg and/or antihypertensive drug treatment. Leptin was measured by radioimmunoassay. Results: After an average 4.4-year follow up (minimum 2 - maximum 7 years), 106 (17.6%) new cases of hypertension were identified. At baseline, participants who developed hypertension were older, and had higher systolic BP and higher total cholesterol compared to participants who remained normotensive. Baseline serum leptin levels were higher in participants who developed hypertension compared to persistent normotensives [median (25(th)- 75(th)range)] [8.8(5-16) vs. 7(4-11) ng/mL, P=0.002]. In logistic regression models, leptin (log-transformed) predicted incident hypertension before and after adjustments for baseline age, BMI, systolic BP, total cholesterol, medications, and previous cardiovascular disease (OR 1.75 95%CI 1.17-2.61, P = 0.006). This association persisted after exclusion of 45 obese participants. Conclusion: Higher leptin levels were independently associated with increased odds of incident hypertension in older adults.

53: Microscopy research and technique, 2010 Feb 9, 31(1)
Leptin-like immunoreactivity in the muscle of juvenile sea bass (Dicentrarchus labrax).

[Abstract]The mammalian hormone, leptin, is mainly synthesized in adipose tissue along with other tissues. Leptin plays a role in numerous processes such as in the control of food intake, homeostasis, immune function and reproduction. In this study, we detected and localized leptin immunoreactivity to the muscle of early juvenile sea bass (Dicentrarchus labrax) by Western blot analysis and immunohistochemistry. A leptin immunopositive band with a molecular weight of approximately 16 kDa, corresponding to mammalian leptin, was identified in trunk skeletal muscle homogenate. Furthermore, leptin immunopositive cells were detected in the endomysium of skeletal muscular fibers. These cells showed immunostained cytoplasmic granules and roundish and oval nuclei. The most intense immunostaining was observed in the endomysial space among the superficial red muscular fibers of the trunk. These findings suggest that in early juvenile sea bass, leptin is mostly produced by skeletal muscles. Therefore, during the developmental stage lacking adipose tissue, skeletal muscles can be considered an important source of leptin. As already suggested in mammals, we can hypothesize the potential roles of leptin not only in energy expenditure for muscle contraction but also during muscle differentiation and growth. Microsc. Res. Tech., 2010. (c) 2010 Wiley-Liss, Inc.

54: The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 2010 Feb 9, 31(1)
Plasma Leptin Concentration in Dogs with Diabetes Mellitus.

[Abstract]The plasma leptin concentration was evaluated in dogs with diabetes mellitus. Twenty normal and sixteen diabetic dogs were divided into nonobese and obese groups based on body condition score, respectively. The obese normal dogs had significantly higher plasma leptin concentrations than the nonobese normal dogs, whereas there was no significant difference between the nonobese and obese diabetic dogs. In addition, the plasma leptin concentration in the obese diabetic dogs was significantly lower than that in the obese normal dogs. In conclusion, the plasma leptin concentrations in the diabetic dogs were affected by factors other than adiposity.

55: European journal of endocrinology / European Federation of Endocrine Societies, 2010 Feb 9, 31(1)
Increased circulating adiponectin levels and decreased leptin/soluble leptin receptor ratio throughout puberty in female ballet dancers: Association with body composition and the delay in puberty.

[Abstract]Introduction Ballet dancers (BD) have a negative energy balance related to physical training that results in alterations in body composition, sexual development and adipokine secretion. Our aims were to study anthropometric parameters, body composition and their relationship with adipokines throughout pubertal development. Subjects and methods We carried out a prospective follow-up study of 22 female Caucasian BD (Tanner II stage) followed throughout puberty. Nutritional status was determined by measurement of height, weight and body mass index (BMI). We calculated growth velocity, bone maturity and body composition at Tanner stages II, III and V by DXA. Circulating leptin, adiponectin and soluble leptin receptor (sObR) levels were determined. Results Ballet dancers presented a delay in skeletal maturation during puberty, without affectation of final height. Energy intake was deficient according to their physical exercise and they had a delay of 1 year in the mean age of menarche. Leptin levels were decreased, whereas sObR and adiponectin levels were increased throughout puberty. The percentage of trunk fat, total fat mass and fat of the extremities was decreased throughout the study period (p<0.01). Lean mass was increased in the lower extremities and bone mineral density was normal. Conclusion A negative energy balance together with maintained physical exercise induced modifications in body composition in BD. Changes in leptin and adiponectin levels appear to be more related to total fat content than to BMI. Furthermore, the onset and delayed progress of puberty may be related with an inadequate energy balance due to increased exercise.

56: Arthritis research & therapy, 2010 Feb 8, 12(1)
Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression.

[Abstract]ABSTRACT: INTRODUCTION: Leptin is a peptide hormone with a role in bone metabolism and rheumatic diseases. The subchondral bone tissue plays a prominent role in the pathophysiology of osteoarthritis (OA), related to abnormal osteoblast (Ob) differentiation. Although leptin promotes the differentiation of Ob under normal condition, a role for leptin in OA Ob has not been demonstrated. Here we determined if endogenous leptin produced by OA Ob could be responsible for the expression of the abnormal phenotypic biomarkers observed in OA Ob. METHODS: We prepared primary normal and OA Ob from subchondral bone of tibial plateaus removed for knee surgery of OA patients or at autopsy. We determined the production of leptin and of the long, biologically active, leptin receptors (OB-Rb) using RT-PCR, ELISA and Western blot analysis. We determined the effect of leptin on cell proliferation by BrdU incorporation and MTT assays, and we determined by Western blot analysis phospho 42/44 MAPK (p42/44 Erk1/2) and phospho p38 levels. We then determined the effect of the addition of exogenous leptin, leptin receptor antagonists, inhibitors of leptin signaling or siRNA techniques on the phenotypic features of OA Ob. Phenotypic features of Ob were determined by measuring alkaline phosphatase activity (ALP), osteocalcin release (OC), collagen type 1 production (CICP) and of Transforming growth factor-beta1 (TGF-beta1). RESULTS: Leptin expression was increased ~5-fold and protein levels ~2-fold in OA Ob compared to normal. Leptin stimulated its own expression and the expression of OB-Rb in OA Ob. Leptin dose-dependently stimulated cell proliferation of OA Ob and also increased phosphorylated p42/44 Erk1/2 and p38 levels. Inactivating antibodies against leptin reduced ALP, OC, CICP and TGF-beta1 levels in OA Ob. Tyrphostin (AG490) and piceatannol (Pce), inhibitors of leptin signaling, reproduced this effect. Inhibition of endogenous leptin levels using siRNA for leptin or inhibiting leptin signaling using siRNA for OB-Rb expression both reduced ALP and OC about 60%. Exogenous leptin addition stimulated ALP, yet this failed to further increase OC or CICP. CONCLUSIONS: These results suggest that abnormal production of leptin by OA Ob could be responsible, in part, for the elevated levels of ALP, OC, collagen type 1 and TGF-beta1 observed in these cells compared to normal. Leptin also stimulated cell proliferation, and Erk 1/2 and p38 signaling. Taken together, these data suggest leptin could contribute to abnormal osteoblast function in OA.

57: General and comparative endocrinology, 2010 May 15, 167(1)
Regional and temporal differences in leptin signaling in rat brain.

[Abstract]Leptin regulates energy homeostasis through activation of different hypothalamic pathways. Evidence indicates that leptin is a pleiotropic hormone that acts on many brain areas, altering food intake, metabolism, and locomotion, among other functions. Because short-term effects of leptin infusion and intracellular pathways in other brain areas involved in food regulation have not been thoroughly analysed, we have studied the acute effect of intracerebroventricular leptin administration on the levels of the long form of leptin receptor (Ob-Rb), as well as on activation of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular regulated kinases (ERKs) and levels of suppressor of cytokine signaling-3 (SOCS3) in the hypothalamus, hippocampus, frontal cortex and cerebellum of adult male Wistar rats at 15min, 1 and 6h. The levels of Ob-Rb increased at 6h in hypothalamus only. Leptin activated the JAK2/STAT3 pathway in all areas, although in a temporally specific pattern. In contrast, this hormone decreased Akt activation in hypothalamus, hippocampus and cerebellum and ERK activation in frontal cortex, while it increased ERK activation in hypothalamus and hippocampus. These differences in modulation of Ob-Rb levels and signaling indicate that the rapid effects of leptin in non-hypothalamic areas are mediated, at least in part, through the intracellular pathways involved in hypothalamic energy balance, but in a temporally specific manner.

58: Medical hypotheses, 2010 Jun, 74(6)
The neuroprotective effect of intranasally applied leptin against hypoxic neuronal injury.

[Abstract]Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.e., excitotoxicity, oxidative stress and apoptosis. All these three mechanisms propagate through distinctive and mutual exclusive signal transduction pathway and contribute to the neuronal loss following the initial hypoxic-ischemic brain injury. Thus, the ideal therapeutic intervention against the hypoxic-ischemic neuronal injury should aim to prevent all three mechanisms of the neuronal death in a concerted effort. Recent studies demonstrated that intranasally administered leptin results in supra-physiological leptin levels at various regions of the brain (including hippocampus) within 30min of administration. We consider leptin to be an ideal neuroprotective agent, having targeted excitotoxicity (directly, by inhibiting AMDA and NMDA) oxidative stress (indirectly, by HIF1 mediation) and apoptosis (directly, by activating ERK 1/2 pathway) and hypothesize that intranasally administered leptin has neuroprotective effect against the neuronal hypoxic injury. If our hypothesis is confirmed, leptin administered before and/or soon after hypoxic injury, may be effective in minimizing the devastating sequelae of such event.

59: Hormones and behavior, 2010 Jan 22, 30(4)
Maternal deprivation induces a rapid decline in circulating leptin levels and sexually dimorphic modifications in hypothalamic trophic factors and cell turnover.

[Abstract]Pathological outcomes, including metabolic and endocrine disturbances, of maternal deprivation (MD) in Wistar rats depend on gender and the timing of deprivation during development. We analyzed the effect of MD between postnatal days 9 and 10, a critical period in hypothalamic development, on circulating hormones and local production of trophic factors involved in this process, as well as on markers of cell turnover and maturation. Males and females were studied 12 and 24 hours after MD and 12 hours (MD36) after returning the dam to her pups. Circulating corticosterone levels were increased and glucose and leptin levels decreased throughout the study in both sexes. Hypothalamic mRNA levels of leptin receptor increased significantly at MD24 in both sexes, normalizing in females at MD36, but not in males. In male rats insulin-like growth factor mRNA levels were significantly decreased at MD24 and brain derived neurotrophic factor mRNA levels decreased at MD12 and MD24, with both trophic factors unaffected in females. In males cell proliferation was significantly decreased at MD36, as were the glial structural proteins, glial fibrillary acidic protein and vimentin. In females, nestin levels decreased significantly at MD24. These results indicate that MD differently affects trophic factors and cell-turnover in the hypothalamus of males and females, which may underlie the sex differences seen in the endocrine and metabolic outcome.

60: Neuroscience letters, 2010 Mar 3, 471(2)
Leptin-sensitive neurons in mouse preoptic area express alpha(1A)- and alpha(2A)-adrenergic receptor isoforms.

[Abstract]Leptin binding to its functional receptor stimulates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway, finally resulting in nuclear translocation of the phosphorylated STAT3 (P-STAT3). Systemic treatment with leptin (3mg/kg; intraperitoneal injection) induced the appearance of P-STAT3-immunoreactive cells in adult mouse preoptic area (POA). Here we show that the vast majority of leptin-responsive cells were located in medial POA (mPOA), followed by the median preoptic nucleus. Rare, scattered and weakly stained cells were found in ventromedial preoptic nucleus and lateral preoptic area. Co-localization studies disclosed that mPOA leptin-responsive cells were neurons, and that a large proportion expressed the alpha(1A)- and/or alpha(2A)-adrenergic receptor (AR) isoforms. Although understanding the functional relevance of leptin-responsive POA neurons requires further investigation, the finding that they bear alpha-ARs suggests that they may be targeted by the ascending noradrenergic system, which densely innervates the mPOA, and thus be involved in thermoregulation, arousal and/or the sleep-wake cycle.

61: American journal of reproductive immunology (New York, N.Y. : 1989), 2010 Mar 1, 63(3)
Leptin on peritoneal macrophages of patients with endometriosis.

[Abstract]Problem The expression of cyclooxygenase (COX)-2 is considered as a marker of macrophage activation and has been implicated in the development of endometriosis. Leptin is an immunomodulator, which may also affect the development of endometriosis. However, how leptin contributes to these pathological processes has not been completely understood. The aim of this study was to investigate the effects of leptin on peritoneal macrophages and its relationship with endometriosis. Methods of study Peritoneal fluid from 60 women of reproductive age was obtained while they underwent laparoscopy. Forty patients had endometriosis and 20 patients did not have endometriosis. The concentration of leptin in the peritoneal fluid and prostaglandin F(2alpha) levels was measured by ELISA, and the other protein expression using Western blot when peritoneal macrophages were stimulated with leptin. Results Concentration of leptin in peritoneal fluid was increased in patients with endometriosis compared with disease-free normal control. Functional leptin receptor was present in peritoneal macrophages. Treatment of peritoneal macrophages with leptin induced COX-2 expression. Production of prostaglandin F(2alpha) by peritoneal macrophages was increased after leptin stimulation in women with endometriosis. Conclusion Elevated concentration of leptin in peritoneal fluid may contribute to the pathological process of endometriosis through activation of peritoneal macrophages.

62: Endocrinology, 2010 Feb, 151(2)
Nutritional programming affects hypothalamic organization and early response to leptin.

[Abstract]Nutritional programming, taking place in utero or early after birth, is closely linked with metabolic and appetite disorders in adulthood. Following the hypothesis that nutritional programming impacts hypothalamic neuronal organization, we report on discrepancies of multiple molecular and cellular early events that take place in the hypothalamus of rats submitted to intrauterine growth restriction (IUGR). Expression screening performed on hypothalami from IUGR rats at birth and at postnatal d 12 identified changes in gene expression of neurodevelopmental process (cell differentiation and cytoskeleton organization). Additionally, a slight reduction of agouti-related protein and a strong reduction of alpha-MSH-immunoreactive efferent fibers were demonstrated in the paraventricular nucleus of IUGR rats. Rapid catch-up growth of IUGR rats, 5 d after birth, had a positive effect on neurodevelopmental factors and on neuronal projections emanating from the arcuate nucleus. The molecular and cellular anomalies detected in IUGR rats can be related to the reduced and delayed plasma leptin surge from d 0-16 when compared with control and IUGR rats with catch-up growth. However, the ability of leptin to activate intracellular signaling in arcuate nucleus neurons was not reduced in IUGR rats. Other mechanism such as epigenetic regulation of the major appetite-regulating neuropeptides genes was analyzed in parallel with their mRNA expression during postnatal development. This study reveals the importance of an early catch-up growth that reduces abnormal organization of hypothalamic pathways involved in energy homeostasis, whereas protein restriction, maintained during postnatal development leads to an important immaturity of the hypothalamus.

63: Physiological genomics, 2009 Dec 8, 59(1)
Differential effects of leptin receptor mutation on male and female BBDR.Gimap5-/Gimap5- spontaneously diabetic rats.

[Abstract]Rodents homozygous for autosomal leptin receptor gene mutations not only become obese, insulin resistant, and hyperleptinemic but also develop a dysregulated immune system. Using marker assisted breeding to introgress the Koletsky rat leptin receptor mutant (lepr-/lepr-), we developed a novel congenic BBDR.(lepr-/lepr-) rat line to study the development of obesity and type 2 diabetes (T2D) in the BioBreeding (BB) diabetes resistant (DR) rat. While heterozygous lepr (-/+) or homozygous (+/+) BBDR rats remained lean and metabolically normal, at 3 weeks of age all of the BBDR.(lepr-/lepr-) rats were obese without hyperglycemia. Between 45-70 days of age, male but not female obese rats developed T2D. We had previously developed congenic BBDR.(Gimap5-/Gimap5-) rats, which carry an autosomal frame shift mutation in the Gimap5 gene linked to lymphopenia and spontaneous development of type 1 diabetes (T1D) without gender differences. As the autoimmune-mediated destruction of the pancreatic islet beta cells may be affected not only by obesity but also by the absent of leptin receptor signaling, we next generated BBDR.(lepr-/lepr-, Gimap5-/Gimap5-) double congenic rats carrying the mutation for Gimap5 and T1D as well as the Lepr mutation for obesity and T2D. The hyperleptinemia rescued end stage islets in BBDR.(lepr-/lepr-, Gimap5-/Gimap5-) congenic rats and induced an increase in islet size in both genders, while T1D development was delayed and reduced only in females. These results demonstrate that obesity and T2D induced by introgression of the Koletsky leptin receptor mutation in the BBDR rat results in islet expansion associated with protection from T1D in female but not male BBDR.(lepr-/lepr-, Gimap5-/Gimap5-) congenic rats. The BBDR.(lepr-/lepr-, Gimap5-/Gimap5-) congenic rats should prove valuable to study interactions between lack of leptin receptor signaling, obesity, and gender-specific T2D and T1D. Key words: Obesity, diabetes, islets inflammation, lymphopenia.

64: Forum of nutrition, 2010, 63(1)
Leptin-Signaling Pathways and Leptin Resistance.

[Abstract]Leptin acts as an anorexigenic hormone in the brain, where the long form of the leptin receptor (LRb) is widely expressed in hypothalamic and extra-hypothalamic sites that are known to participate in diverse feeding circuits. The important role of leptin in energy homeostasis is demonstrated by the profound hyperphagia and morbid obesity in humans and rodents null for leptin or LRb. However, common forms of obesity are associated with high leptin levels and a failure to respond effectively to exogenous leptin; indicating a state of leptin resistance. Leptin resistance is thought to be an important component in the development of obesity. Several defects may contribute to the leptin resistant state, including a defective leptin transport across the blood-brain barrier, which reduces the availability of leptin at its receptor. Furthermore, defects in LRb signal transduction involving reduced LRb expression or the induction of feedback inhibitors have been found in leptin resistance; these defects are commonly termed cellular leptin resistance,. Finally, reduced leptin action can result in the disruption of proper neuronal interactions, by altering neuronal wiring. Interestingly, some leptin functions remain intact in the leptin-resistant state, such as cardiovascular leptin effects. The appearance of selective leptin resistance is mirrored by the observation that cellular leptin resistance has been found only in some subpopulations of hypothalamic LRb neurons. Current efforts to dissect leptin function in specific populations of LRb neurons will increase our understanding of these complexities of leptin physiology.

65: Clinical nephrology, 2009 Dec, 72(6)
Effective removal of leptin via hemodiafiltration with on-line endogenous reinfusion therapy.

[Abstract]Aims: Leptin is a middle-molecular weight uremic toxin. Hemodiafiltration with on-line endogenous reinfusion (HFR) is a novel dialytic method combining the processes of diffusion, convection and adsorption. We performed a prospective crossover study of patients with end-stage renal disease to investigate the effect of HFR therapy on the level of leptin as compared to conventional low flux hemodialysis (LHD). Methods: Eleven stable hemodialysis patients were treated with LHD for 12 weeks and then treated with HFR (SG30 Plus; Sorin Group Italia S.r.1, Mirandola, Italy) for 12 weeks. Results: After 12 weeks of HFR treatment, serum leptin levels significantly decreased (17.1 (2.66 - 39.5) at Week 12 vs. 12.3 (1.80 - 24.3) ng/ml at Week 24, p = 0.014). Although serum adiponectin levels also decreased (1.66 (1.44 - 1.86) at Week 12 vs. 1.12 (0.79 - 1.34) g/ml at Week 24, p = 0.001), the ratio of leptin to adiponectin did not increase after HFR treatment. Serum beta2-microglobulin (beta2M) levels significantly decreased (37.7 (29.8 - 42.6) at Week 12 vs. 28.3 (26.5 - 32.2) mg/dl at Week 24, p = 0.002). Dry weight, Kt/V(urea), normalized protein equivalent of nitrogen appearance, subjective global assessment, and serum albumin levels of the patients were not changed after HFR treatment. There was no difference in the serum levels of C-reactive protein or interleukin-6 between Week 12 and Week 24. Conclusions: The results of our study indicate that HFR may be a better therapy than LHD for removal of middle-molecular-weight uremic toxins such as leptin and b2M.

66: European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 2009 Nov 18, 276(1675)
The relation of leptin and adiponectin with breast density among premenopausal women.

[Abstract]The adipocytokine leptin may increase breast cancer risk, while adiponectin may be protective. We examined the association of the two circulating markers with mammographic density, a strong predictor of breast cancer risk. For 183 premenopausal participants of a nutritional trial, mammograms performed at baseline, year 1 and year 2 were assessed for density using a computer-assisted method. Serum samples obtained at the same time were analyzed for leptin and adiponectin by enzyme-linked immunosorbent assay. We applied mixed models to incorporate the repeated measurements while adjusting for confounders including body mass index (BMI). At baseline, the mean age of the participants was 42.6+/-2.9 years; 40% were of Asian ancestry. Leptin was lower and adiponectin higher in normal weight than overweight women. Neither marker was related to absolute breast density. The significant inverse association of leptin with percent density disappeared when BMI was added to the model. After stratification by weight, percent density decreased with higher leptin levels in normal weight women, whereas it increased among overweight participants. After adjustment for BMI, the positive association between percent density and adiponectin was greatly reduced and no longer significant. These results do not support a strong association of leptin or adiponectin with breast cancer risk as assessed by mammographic density. In contrast, the findings suggest the possibility that the inverse association of BMI with breast cancer risk in premenopausal women is mediated by adipocytokines.

67: International journal of cancer. Journal international du cancer, 2010 Jul 1, 127(1)
Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells.

[Abstract]Adipositas correlates with an enhanced risk of developing malignant diseases such as breast cancer, endometrial tumor or prostate carcinoma, but the molecular basis for this is not well understood. Potential mechanisms include increased bioavailability of adipocytokines (e.g. leptin) and steroid hormones. Here, we investigated cross-talk between ERalpha (estrogen receptor alpha) and leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), a transactivator of important oncogenes. Upon leptin binding to its receptor Ob-RL (obesity receptor), STAT3 tyrosine phosphorylation and transactivation activity were enhanced by simultaneously expressing ERalpha. Downregulation of ERalpha using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERalpha ligands estradiol (E2) or estrogen antagonists ICI182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERalpha ligands. We also detected ERalpha binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ERalpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ERalpha-dependent development of malignant diseases.

68: Endocrine, 2009 Oct 28, 8(19)
Inhibition of SOCS-3 in adipocytes of rats with diet-induced obesity increases leptin-mediated fatty acid oxidation.

[Abstract]Rats with diet-induced obesity (DIO) usually experience hyperleptinemia. Thus, leptin produced by adipocytes does not deplete adipocyte fat, which implying a leptin resistance in adipocytes during overnutrition. Here, we induced hyperleptinemia in rats by feeding them a diet consisting of 45% fat. In epididymal adipose tissues, the mRNA and protein levels of a putative leptin resistant factor, suppressor of cytokine signaling 3 (SOCS-3), were increased. The mRNA levels of SOCS-3 in adipocytes differentiated from adipose-derived stromal cells (ADSCs) were higher in DIO rats than in rats on a 10% fat diet. Using SOCS-3 short hairpin RNA lentivirus interference, we found decreased expression of acetyl-CoA carboxylase mRNA (a marker of de novo lipogenesis) and increased expression of acetyl-CoA oxidase mRNA (a marker of fat oxidation) in SOCS-3-knockdown adipocytes after incubation with 50 nM leptin for 6 h. We conclude that the SOCS-3 knockdown may have increased the leptin-mediated in situ fatty acid oxidation in the DIO adipocytes, and therefore, SOCS-3 might be an excellent target for therapeutic intervention for obesity.

69: The Journal of clinical endocrinology and metabolism, 2009 Oct 26, 1295(19)
Serum Markers of Bone Turnover Are Increased at Six and 18 Months after Roux-En-Y Bariatric Surgery: Correlation with the Reduction in Leptin.

[Abstract]Objective: The aim of the study was to examine serum markers of bone turnover at 6 and 18 months after Roux-en-Y gastric bypass surgery. Participants: Ten women and 10 men [body mass index (BMI), 50.2 +/- 8.4 kg/m(2)] were studied at 6 months; 10 women and nine men (BMI, 47.2 +/- 6.6 kg/m(2)) were studied at 18 months after surgery. Main Outcome Measures: Serum osteocalcin, bone specific alkaline phosphatase (BAP), N-telopeptide of type 1 collagen (NTX), PTH, 25-hydroxy vitamin D, and leptin were measured. Results: BMI was reduced 32.7 +/- 6.2% at 6 months after surgery. Serum osteocalcin (6.9 +/- 2.4 to 10.9 +/- 2.6 ng/ml; P < 0.0001), BAP (14.2 +/- 3.7 to 16.4 +/- 4.5 ng/ml; P = 0.04), and NTX (10.9 +/- 1.7 to 19.6 +/- 5.3 nM bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (16.0 +/- 8.9 vs. 26.9 +/- 10.6 ng/ml; P <0.0001). The increase in NTX correlated with reduction in serum leptin (r = 0.58; P = 0.007). BMI was reduced 40.9 +/- 7.5% at 18 months after surgery. Serum BAP (17.6 +/- 5.3 to 22.2 +/- 7.8 ng/ml; P = 0.0017) and NTX (10.8 +/- 2.7 to 16.9 +/- 5.5 nM bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (17.7 +/- 7.6 to 25.6 +/- 6.8 ng/ml; P < 0.0001). The increase in NTX correlated with reduction in BMI (r = 0.58; P = 0.009) and leptin (r = 0.45; P = 0.04) and the increase in serum 25-hydroxy vitamin D (r = 0.43; P = 0.05). In multiple regression (adjusted model R(2) 0.263; P = 0.013), reduction in leptin was a significant predictor of increase in NTX (P = 0.016), but changes in BMI and 25-hydroxy vitamin D were not. Conclusions: Weight loss after bariatric surgery is associated with long-term increase in serum markers of bone turnover. The increase in NTX is related to the decrease in leptin, which may signal caloric restriction to the skeleton.

70: General and comparative endocrinology, 2010 Mar 1, 166(1)
Gene structure, recombinant expression and functional characterization of grass carp leptin.

[Abstract]Leptin is an important hormone for the regulation of food intake, energy expenditure and reproduction in mammals, but information regarding its role in teleosts remains scant. In the present study, the gene structures of grass carp (Ctenopharyngodon idellus) and silver carp (Hypophthalmichthys molitrix) leptins were characterized. Recombinant grass carp leptin (rgc-LEP) was expressed in Escherichia coli and purified, and identified by mass spectrometric analysis. A strong anorexic effect on food intake was observed in grass carp on the first day after intraperitoneal (IP) injection of rgc-LEP, but not during the following days. Body weight of the leptin group (LEP group) and the pair-fed group (PF group) showed no difference throughout the experimental period. The acute and chronic effects on the expression of key genes correlating to food intake, energy expenditure, lipid metabolism and digestion were further characterized by real-time PCR. Accordingly, the mRNA levels of neuropeptide Y (NPY), Stearoyl-CoA desaturase 1 (SCD1) and lipoprotein lipase (LPL) were significantly reduced whereas the mRNA levels of uncoupling protein 2 (UCP2), bile salt-activated lipase (BSAL) and fatty acid elongase (ELO) were significantly elevated on the first day after injection. No effect on the expression of these genes (except LPL) was observed on day 13. In contrast to the down-regulation by exogenous leptin in mammals, the mRNA level of grass carp leptin was elevated 5.76-fold on the first day after rgc-LEP treatment. Our results suggest that leptin has an acute effect on the regulation of food intake, energy expenditure and lipid metabolism in grass carp, but the effect can be rapidly counteracted through mechanisms that are currently unknown.

71: Endocrine, 2009 Oct 24, 1295(19)
Administration of human leptin differentially affects parameters of cortisol secretion in socially housed female rhesus monkeys.

[Abstract]Chronic exposure to psychosocial stress may lead to a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis that results in a number of adverse health outcomes. The fat-derived hormone leptin has been indicated as a potential key component to maintaining homeostasis by enhancing glucocorticoid negative feedback. Using an established model of nonhuman primate social stress, notably social subordination, this study examined the effects of continuous leptin administration on cortisol secretion in female rhesus monkeys. The 20 subjects were maintained in stable five-member social groups with established dominance hierarchies. All females were ovariectomized but received estradiol throughout the study to maintain serum concentrations at early follicular phase levels. Three parameters of cortisol secretion were examined in dominant and subordinate females during control and leptin-treatment conditions: diurnal cortisol secretion; response to a dexamethasone suppression test; and response to a brief separation from their social group. We hypothesized that leptin supplementation would attenuate the hypercortisolemia characteristic of subordinate females. During baseline conditions, subordinate female rhesus monkeys had significantly lower levels of serum leptin compared with more dominant monkeys and were less sensitive to glucocorticoid negative feedback. Exogenous administration of leptin improved glucocorticoid negative feedback in subordinate females and decreased morning cortisol in all animals. However, there were no status differences in response to a social separation test and diurnal rhythm in cortisol during baseline conditions. However, leptin administration did not attenuate the increase in cortisol in response to a social separation. The data presented in this study demonstrate that leptin can attenuate several parameters of cortisol secretion in female rhesus monkeys and thus may play a role in the response of the adrenal glands to socio-environmental stimuli.

72: General and comparative endocrinology, 2010 May 15, 167(1)
Is there a leptin gene in the chicken genome? Lessons from phylogenetics, bioinformatics and genomics.

[Abstract]Leptin regulates energy homeostasis through activation of different hypothalamic pathways. Evidence indicates that leptin is a pleiotropic hormone that acts on many brain areas, altering food intake, metabolism, and locomotion, among other functions. Because short-term effects of leptin infusion and intracellular pathways in other brain areas involved in food regulation have not been thoroughly analysed, we have studied the acute effect of intracerebroventricular leptin administration on the levels of the long form of leptin receptor (Ob-Rb), as well as on activation of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular regulated kinases (ERKs) and levels of suppressor of cytokine signaling-3 (SOCS3) in the hypothalamus, hippocampus, frontal cortex and cerebellum of adult male Wistar rats at 15min, 1 and 6h. The levels of Ob-Rb increased at 6h in hypothalamus only. Leptin activated the JAK2/STAT3 pathway in all areas, although in a temporally specific pattern. In contrast, this hormone decreased Akt activation in hypothalamus, hippocampus and cerebellum and ERK activation in frontal cortex, while it increased ERK activation in hypothalamus and hippocampus. These differences in modulation of Ob-Rb levels and signaling indicate that the rapid effects of leptin in non-hypothalamic areas are mediated, at least in part, through the intracellular pathways involved in hypothalamic energy balance, but in a temporally specific manner.

73: Current opinion in nephrology and hypertension, 2009 Oct 21, 7(1)
Obesity hypertension: the emerging role of leptin in renal and cardiovascular dyshomeostasis.

[Abstract]PURPOSE OF REVIEW: Adipose tissue is now considered to be an active physiologic system operating in concert with multiple other organs. Leptin is a peptide hormone that is primarily synthesized and secreted by adipose tissue whose principal action is the control of appetite and energy balance. However, current information suggests that leptin exerts pleiotropic effects on several organ systems. Herein, we review the potential role of leptin in cardiovascular and renal physiological conditions as well as pathophysiological situations including obesity and hypertension. RECENT FINDINGS: Increasing evidence suggests that leptin may function as a pressure and volume-regulating factor under conditions of health; however, in situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for adverse renal, vascular and cardiac remodeling. SUMMARY: Adipose tissue should be regarded as a potentially important mediator of cardiorenal physiology. Further research awaits the characterization of additional mechanisms of action of leptin, including its interface with other important endocrine and hemodynamic sodium-volume regulatory systems, in both health and disease, particularly in obesity and related comorbidities. This information could lead to the development of leptin analogues as well as leptin receptor blockers that given specific circumstances could optimize the beneficial actions of the hormone and minimize its deleterious effects.

74: Endocrine journal, 2009 Oct 23, 1295(19)
Role of Central Leptin Signaling in Renal Macrophage Infiltration.

[Abstract]Monocytes/macrophages are key mediators of wound repair, tissue remodeling, and inflammation. However, the molecular mechanisms underlying macrophage recruitment to the site of inflammation is not fully understood. Leptin acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. The leptin receptor, a single transmembrane protein that belongs to the gp130 family of cytokine receptor superfamily, is expressed not only in the hypothalamus but in a variety of peripheral tissues, suggesting the role of leptin as a pro-inflammatory adipocytokine in peripheral tissues. Here, we show that deficiency of leptin signaling reduces renal macrophage infiltration after unilateral ureteral obstruction (UUO). Bone marrow transplantation studies using leptin signaling-deficient db/db mice revealed that leptin signaling in bone marrow cells may not play a major role in the UUO-induced renal macrophage infiltration. Interestingly, central leptin administration reverses the otherwise reduced UUO-induced renal macrophage infiltration in leptindeficient ob/ob mice. This is effectively abolished by central co-administration of SHU9119, a melanocortin-3 receptor/melanocortin-4 receptor antagonist. This study demonstrates that central leptin administration in ob/ ob mice accelerates renal macrophage infiltration through the melanocortin system, thereby suggesting that the central nervous system, which is inherent to integrate information from throughout the organism, is able to control peripheral inflammation.

75: Journal of applied toxicology : JAT, 2009 Oct 21, 7(1)
Metals in human placenta: focus on the effects of cadmium on steroids hormones and leptin.

[Abstract]Cadmium and other metallic ions can act as metalloestrogens and endocrine disruptors of reproductive tissues and fetal development in mammals, including humans. The detrimental effects occur with respect to the synthesis of both steroid and polypeptide hormones in the placenta. Leptin is produced by the trophoblast and may regulate fetal organogenesis and development. In human term placentas, concentrations of toxic metals and their effects on steroidogenesis were assessed in healthy parturients (109 non-smokers and 99 smokers) in relation to tobacco smoking. Trace elements (cadmium, lead, iron, zinc and copper) were analyzed in placentas using atomic absorption spectroscopy, and steroid hormones (progesterone and estradiol) were assayed in placental samples by an enzyme-immunometric method. Cadmium concentrations were doubled in placentas of smokers as compared with non-smokers, and placental lead and zinc concentrations increased significantly. Placental concentrations of iron, copper, progesterone and estradiol did not differ. In addition, human trophoblast cells were co-cultured with 0, 5, 10 or 20 microm CdCl(2) for 96 h and leptin mRNA assessed by quantitative polymerase chain reaction. Leptin mRNA declined dose-responsively as a result of CdCl(2) exposure. Collectively, the results confirm that human placental tissue offers a unique opportunity to biomonitor cadmium exposure in both the maternal and the internal fetal environments. In addition, the results strongly suggest that cadmium may cause a decline in placental leptin synthesis, as we have previously shown for placental progesterone production. This may constitute further evidence of the endocrine-disrupting effects of cadmium, as a constituent of tobacco smoke, on reproduction in women. Copyright (c) 2009 John Wiley & Sons, Ltd.

76: Metabolism: clinical and experimental, 2009 Oct 19, 7(1)
Administration of physiologic levels of triiodothyronine increases leptin expression in calorie-restricted obese rats, but does not influence weight loss.

[Abstract]Obesity has become a major public health problem, most commonly treated via dietary restriction to promote weight loss. Although leptin and thyroid hormones are involved in the regulation of energy balance, the role of these hormones after the stabilization of weight loss remains unclear. This study was designed to analyze the effect of thyroid hormone on sustained weight loss and leptin gene expression in obese animals after a loss of 5% to 10% of body weight. Thirty-day-old male Wistar rats were separated into 4 groups: control, obese, calorie restriction (CR), and calorie restriction with triiodothyronine administration (CRT). The obese group had increased weight and adiposity, leptin and insulin levels, and leptin gene expression. Dietary restriction in the CR group resulted in decreased body weight and adiposity, diminished leptin, and increased thyroid hormone receptor beta expression. The CRT group, submitted to dietary restriction with concomitant administration of a physiologic triiodothyronine dose, had thyroid hormone receptor beta expression at levels comparable with those observed in the control group and simultaneously increased leptin expression as compared with that in the CR group, suggesting that thyroid hormone modulates leptin expression under conditions of calorie restriction. Increased leptin expression in the CRT group did not result in increased circulating leptin or a statistically significant reduction in body weight during the treatment period. These data provide impetus for further study, as a longer treatment period may result in increased circulating leptin and, thus, further reduction in body weight during calorie restriction in an obesity model.

77: Metabolism: clinical and experimental, 2010 Mar, 59(3)
Serum leptin is associated with metabolic syndrome in obese and nonobese Korean populations.

[Abstract]Leptin is mainly secreted from adipose tissue and is known to be associated with cardiovascular diseases. However, there are not many studies on the association between serum leptin and metabolic syndrome. The objective of this study was to determine the association between serum leptin and metabolic syndrome among the Korean adult population. The study population consisted of 3,272 Koreans (men: 1,915, women: 1,357) 30 to 84 years of age who had visited the Health Examination Center. Leptin levels were divided into quintiles and metabolic syndrome was defined by NCEP ATP III. The serum leptin levels increased as the number of components present for metabolic syndrome increased. Controlling for age, smoking, exercise, and LDL cholesterol, subjects with high leptin levels were more likely to have an elevated risk of metabolic syndrome than those with lower levels in both men and women. Subjects in the highest leptin quintile were found to have a higher risk of having metabolic syndrome than those in the lowest quintile (OR = 11.51 for men; OR = 4.65 for women). After further adjustment of the BMI, the risk of metabolic syndrome still increased slightly for men but not for women in increasing leptin categories. This association of leptin levels and metabolic syndrome did not change after stratification into obese and nonobese weight status. Serum leptin is associated with metabolic syndrome in Korean populations independent of body mass index. Thus, the reduction of circulating leptin may confer cardiovascular and metabolic protective effects regardless of weight status.

78: Hypertension, 2009 Oct 19, 7(1)
Relation of Serum Leptin to Blood Pressure of Japanese in Japan and Japanese-Americans in Hawaii.

[Abstract]Data from animal studies clearly indicate an association between leptin and hypertension; results of human studies are less concordant. We investigated the role of leptin in obesity-related higher blood pressure (BP) in Japanese Americans living in Hawaii and Japanese in Japan. Serum leptin and BP were examined by standardized methods in men and women ages 40 to 59 years from 2 population samples, one Japanese American in Hawaii (88 men and 94 women) and the other Japanese in central Japan (123 men and 111 women). Multiple linear regression models were used to assess role of leptin in obesity-related higher BP. Across quartiles of leptin, there were significantly higher mean body mass index levels, systolic BP, and diastolic BP for both sexes and sites (P<0.01 to 0.02). In multivariate regression analyses using all of the data combined, relations of body mass index and leptin to systolic BP and diastolic BP remained significant with the interaction term (body mass indexxlog-leptin) in the models (P<0.01 to <0.05). These findings are consistent with the inference that leptin may be an independent mediator for obesity-related elevations in BP.

79: Psychoneuroendocrinology, 2010 May, 35(4)
Orexin and leptin are associated with nicotine craving: A link between smoking, appetite and reward.

[Abstract]OBJECTIVE: Preclinical data suggest modulating effects of both orexin/hypocretin and leptin on dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role of both peptides in reward function and motivation, and thus in addictive diseases. The aim of this study was to examine the possible association between orexin and leptin, and nicotine craving in smokers in a clinical case-control study under standardized conditions. METHODS: We compared orexin and leptin, ACTH and cortisol plasma concentrations (RIA) between tobacco smokers (n=60) during early nicotine withdrawal and healthy controls (n=64). Motivational aspects of nicotine craving were additionally assessed in the smoking participants using the Questionnaire of Smoking Urges (QSU). RESULTS: As main results we detected a significant negative correlation between orexin plasma concentration and nicotine craving (r=-0.28; p<.05), and a positive association between craving and leptin plasma concentration (r=0.29; p<.05). CONCLUSIONS: Our results show an association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both peptides interfere with the dopaminergic transmission during nicotine withdrawal in a bidirectional manner and, thus, modulate craving for nicotine.

80: General and comparative endocrinology, 2010 Mar 1, 166(1)
Variation in plasma leptin-like immunoreactivity in free-living European starlings (Sturnus vulgaris).

[Abstract]Leptin, a protein hormone secreted by fat cells, is best known for its role as an adiposity signal; however, leptin has diverse physiological roles ranging from regulation of feeding behavior and body weight, to effects on reproduction and immune function. Although leptin has been extensively studied in mammals, the identification and function of leptin in birds remains controversial, and studies have focused on captive or domesticated species. Here, we describe changes in plasma leptin-like immunoreactivity during the reproductive and non-reproductive seasons in free-living female European starlings (Sturnus vulgaris). Plasma leptin-like immunoreactivity was high during egg-laying (27.8+/-2.4ng/mL) and clutch completion (23.8+/-1.6ng/mL), decreased during incubation (13.0+/-1.6ng/mL) and chick-rearing (12.0+/-1.3ng/mL), but was elevated again in non-breeders in November (23.7+/-1.1ng/mL). Although there was marked and consistent variation in total body mass and body composition with breeding stage and season in this population, plasma leptin-like immunoreactivity did not parallel changes in body mass or body composition. These data suggest that the strong positive relationship between plasma leptin-like immunoreactivity and body mass reported for captive birds and mammals does not hold for free-living birds. Rather, among free-living female European starlings, variation in plasma leptin-like immunoreactivity is associated with breeding stage or seasonal variation per se, and we discuss possible mechanisms underlying this variation, focusing on ovarian function and egg production.

81: European journal of endocrinology / European Federation of Endocrine Societies, 2009 Dec, 161(6)
Free leptin index and thyroid function in male highly trained athletes.

[Abstract]Objective Exercise training may cause changes in thyroid function. This thyroid response may be due to exercise-induced modulation of energy metabolism but also of the adipocytes endocrine function. In particular, the role of leptin and of circulating soluble leptin receptor (sOB-R) was unexplored. The aim of this study was to assess the relationships between thyroid function, whole body energy metabolism, and adipokines - mainly leptin and its receptor, sOB-R. Methods We measured serum TSH, free tri-iodothyronine (FT(3)), free thyroxine, leptin, and sOB-R and assessed energy homeostasis by means of indirect calorimetry, in 27 highly trained athletes and 27 sedentary, healthy men. Results TSH-FT(3) ratio was lower in athletes (P<0.03), either in sustained power or anaerobic power-sprint athletes (n=13) or marathon runners (n=14). Whole body respiratory quotient was lower in athletes. Fasting serum sOB-R was higher and leptin lower in athletes than controls. Also serum adiponectin, resistin, and retinol binding protein-4 concentrations were different in athletes than in controls. The ratio between leptin and sOB-R, the free leptin index (FLI), was lower in athletes than in controls (0.025+/-0.014 vs 0.085+/-0.049; P<0.001). In multivariate analysis, FLI retained independent association with TSH-FT(3) ratio. Conclusion Male, elite athletes had lower TSH-FT(3) ratio and FLI than controls while FLI was independently associated with TSH-FT(3) ratio supporting the hypothesis that the level of biologically active leptin is involved in the adaptive response of thyroid function in professional athletes.

82: Hypertension, 2009 Nov, 54(5)
Leptin impairs cardiovagal baroreflex function at the level of the solitary tract nucleus.

[Abstract]Circulating leptin is elevated in some forms of obesity-related hypertension, associated with impaired baroreflex function. Leptin receptors are present on vagal afferent fibers and neurons within the solitary tract nucleus, providing an anatomic distribution consistent with baroreflex modulation. Although solitary tract nucleus microinjection of 144 fmol/60 nL of leptin had no significant effect on baroreflex sensitivity for control of the heart rate in urethane/chloralose-anesthetized Sprague-Dawley rats, 500 fmol of leptin impaired baroreflex sensitivity for bradycardia in response to increases in pressure (1.15+/-0.04 versus 0.52+/-0.12 ms/mm Hg; P<0.01). Transgenic ASrAOGEN rats with low brain angiotensinogen have an upregulation of the leptin receptor and p85 alpha mRNA in the dorsal medulla relative to Sprague-Dawley rats. Consistent with these observations, the response to leptin was enhanced in ASrAOGEN rats, because both the 144-fmol (1.46+/-0.08 versus 0.75+/-0.10 ms/mm Hg; P<0.001) and 500-fmol (1.36+/-0.32 versus 0.44+/-0.06 ms/mm Hg; P<0.05) leptin microinjections impaired baroreflex sensitivity. At these doses, leptin microinjection had no effect on resting pressure, heart rate, or the tachycardic response to decreases in pressure in Sprague-Dawley or ASrAOGEN rats. Thus, exogenous leptin at sites within the solitary tract nucleus impairs the baroreflex sensitivity for bradycardia induced by increases in arterial pressure, consistent with a permissive role in mediating increases in arterial pressure. Baroreflex inhibition was enhanced in animals with evidence of increased leptin receptor and relevant signaling pathway mRNA.

83: Diabetes, 2009 Dec, 58(12)
Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues.

[Abstract]OBJECTIVE The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues. RESEARCH DESIGN AND METHODS Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[(3)H]deoxy-d-glucose method. RESULTS Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect. CONCLUSIONS The VMH mediates leptin- and MT-II-induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II-induced glucose uptake in peripheral tissues.

84: Peptides, 2009 Dec, 30(12)
Leptin receptor mRNA in rat brain astrocytes.

[Abstract]We recently reported that mouse astrocytes express leptin receptors (ObR), and that obesity induces upregulation of astrocytic ObR. To provide further evidence of the importance of astrocytic ObR expression, we performed double-labeling fluorescent in situ hybridization (FISH) and immunohistochemistry in the rat hypothalamus. Laser confocal microscopic image analysis showed that ObR mRNA was present in glial fibrillary acidic protein (+) cells that show distinctive astrocytic morphology as well as in neurons. In addition to the presence of ObR mRNA, ObR protein was shown in both astrocytes and neurons in the rat hypothalamus by double-labeling immunohistochemistry. In cultured rat C6 astrocytoma cells treated with different doses of lipopolysaccharide for 6h, the mRNA for ObRa or ObRb did not show significant changes, as measured by quantitative RT-PCR. However, the protein expression of both ObRa and ObRb, determined by Western blotting, was increased after the C6 cells were treated with either lipopolysaccharide or tumor necrosis factor-alpha. The results indicate that astrocytic ObR expression is present in rats as well as mice, and that it probably plays a role in the neuroinflammatory response.

85: Clinical biochemistry, 2009 Nov, 42(16-17)
Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma-2 gene on obesity risk and leptin levels in a Tunisian population.

[Abstract]OBJECTIVES: This study was undertaken to investigate the impact of the Pro12Ala (rs1801282) polymorphism of the peroxisome proliferator-activated receptor gamma-2 (PPARgamma-2) gene on obesity or body mass index (BMI) and plasma leptin, insulin, adiponectin and lipid levels in a sample of the Tunisian population. DESIGN AND METHODS: The study included 387 obese patients and 288 control subjects. The Pro12Ala genotype was determined by polymerase chain reaction followed by a digestion with the restriction of endonuclease BstUI. RESULTS: In the whole population, there is no significant difference in genotype frequencies of the Pro12Ala polymorphism between obese patients and controls. However, separate analysis by gender revealed that obese men (but not women) had significantly higher frequency of Pro/Ala genotypes compared to controls (12.2% vs. 4.1%; chi(2)=6.76, p=0.009). In comparison to Pro/Pro homozygotes, Ala-allele bearers had a significantly higher risk of obesity [OR (95% CI)=3.26 (1.28-8.33)]. When obese subjects were stratified according to type 2 diabetes status, the association with obesity was only significant in obese non-diabetic patients [OR (95% CI)=3.74 (1.43-9.74), p=0.007]. Additionally, obese male patients carrying the Ala-allele had significantly higher body mass index (p=0.007) and plasma leptin levels (p=0.023) compared to those homozygous for Pro-allele. The significant effect of Pro12Ala polymorphism on plasma leptin levels disappeared after adjustment for age and BMI. CONCLUSION: The present study provides evidence that the Pro12Ala polymorphism of the PPARgamma-2 gene is associated with obesity in non-diabetic men from Tunisian origin.

86: Journal of cellular biochemistry, 2009 Nov 1, 108(4)
Leptin and insulin induce mutual resistance for nitric oxide synthase III activation in adipocytes.

[Abstract]Obesity-induced hyperleptinemia is frequently associated with insulin resistance suggesting a crosstalk between leptin and insulin signaling pathways. Our aim was to determine whether insulin and leptin together interfere on NOS activation in adipocytes. We examined insulin and leptin-induced nitric oxide synthase (NOS) activity, protein amount and NOS III phosphorylation at Ser(1179) in isolated epididymal adipocytes from rat, in the presence or not of inhibitors of kinases implicated in insulin or leptin signaling pathways. Insulin or leptin induced NOS III phosphorylation at Ser(1179) leading to increased NO production in rat adipocytes, in agreement with our previous observations. When insulin and leptin at a concentration found in obese rats (10 ng/ml) were combined, NOS activity was not increased, suggesting a negative crosstalk between insulin and leptin signaling mechanisms. Chemical inhibitors of kinases implicated in signaling pathways of insulin, such as PI-3 kinase, or of leptin, such as JAK-2, did not prevent this negative interaction. When leptin signaling was blocked by PKA inhibitors, insulin-induced NOS activity and NOS III phosphorylation at Ser(1179) was observed. In the presence of leptin and insulin, (i) IRS-1 was phosphorylated on Ser(307) and this effect was prevented by PKA inhibitors, (ii) JAK-2 was dephosphorylated, an effect prevented by SHP-1 inhibitor. A mutual resistance occurs with leptin and insulin. Leptin phosphorylates IRS-1 to induce insulin resistance while insulin dephosphorylates JAK-2 to favor leptin resistance. This interference between insulin and leptin signaling could play a crucial role in insulin- and leptin-resistance correlated with obesity. J. Cell. Biochem. 108: 982-988, 2009. (c) 2009 Wiley-Liss, Inc.

87: European journal of nutrition, 2010 Mar, 49(2)
Dietary sucrose intake is related to serum leptin concentration in overweight pregnant women.

[Abstract]BACKGROUND: Overweight, characterized by low-degree systemic inflammation, predisposes women to impaired glucose metabolism during pregnancy. Adipokine leptin participates in the regulation of energy balance and immune action. AIMS OF THE STUDY: Objective of the study was to evaluate if aberrations in glucose metabolism during pregnancy are related to leptin concentration and whether serum leptin concentration is affected by diet composition. SUBJECTS AND METHODS: Normal-weight (n = 61) and overweight or obese (BMI > 25, n = 42) pregnant women visited study clinic at third trimester of pregnancy and one month postpartum. Serum fasting leptin and insulin as well as plasma glucose concentrations were measured, insulin resistance (HOMA) and sensitivity (QUICKI) calculated, and dietary intake from food records determined. RESULTS: In overweight women leptin concentration was significantly higher both in pregnancy, 45.27 (95% CI 39.40-51.14) ng/ml, and postpartum, 31.84 (27.38-36.30) ng/ml, than in normal-weight women, 31.09 (95% CI 27.80-34.37) ng/ml and 16.23 (13.93-18.53) ng/ml, respectively. Equally, blood glucose concentration during pregnancy was higher, 4.82 (4.67-4.97)mmol/l, and insulin concentration, 15.34 (12.00-18.68) mU/l, more pronounced in overweight compared to normal-weight women, 4.51 (4.42-4.61) mmol/l and 8.28 (7.21-9.36) mU/l, respectively. Significantly higher HOMA and lower QUICKI were also detected in overweight compared to normal-weight women. At third trimester of pregnancy, leptin concentration correlated positively with insulin concentration in normal-weight (r = 0.561, P = 0.002) and overweight women (r = 0.736, P < 0.001), as well as with HOMA (r = 0.568, P = 0.002 and r = 0.731, P < 0.001, respectively) whereas negative association was found with QUICKI in normal-weight (r = -0.484, P = 0.011) and overweight women (r = -0.711, P < 0.001). Importantly, serum leptin concentration was affected by dietary sucrose intake both as quantitatively (r = 0.424, P = 0.009) and relative to energy intake (r = 0.408, P = 0.012) in overweight but not in normal-weight pregnant women. CONCLUSIONS: Overweight-related elevation in serum leptin is associated with impaired regulation of glucose metabolism during pregnancy. The novel finding that dietary sucrose intake is related to serum leptin concentration is in line with the current dietary recommendations to overweight pregnant women with impaired glucose metabolism advising the lower intake of sucrose during pregnancy.

88: American journal of physiology. Endocrinology and metabolism, 2009 Dec, 297(6)
Recent advances in understanding leptin signaling and leptin resistance.

[Abstract]The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.

89: Cancer biology & therapy, 2009 Oct 29, 8(19)
Obesity promotes melanoma tumor growth: Role of leptin.

[Abstract]Epidemiological studies suggest that obesity increases the risk of developing several cancers, including melanoma. Obesity increases the expression of angiogenic factors, such as leptin, that may contribute to tumor growth. However, a direct cause and effect relationship between obesity and tumor growth has not been clearly established and the role of leptin in accelerating tumor growth is unclear. Our objective in the present study was to examine the rate of melanoma tumor growth in lean and obese mice with leptin deficiency or high levels of plasma leptin. We injected 1 x 10(6) B16F10 melanoma cells subcutaneously into lean wild type (WT), obese melanocortin receptor 4 knockout (MC4R(-/-)), which have high leptin levels, obese leptin-deficient (ob(-/-)), pair fed lean ob(-/-), and lean ob(+/-) mice. Mean body weights were 29.7 +/- 0.3 g (WT), 46.3 +/- 1.9 g (MC4R(-/-)), 63.7 +/- 0.9 g (ob(-/-)), 30.5 +/- 1.0 g (pair fed ob(-/-)) and 31.6 +/- 1.7 g (ob(+/-)). Tumors were much larger in the obese leptin deficient ob(-/-) (5.1 +/- 0.9 g) and obese MC4R(-/-) (5.1 +/- 0.7 g) than in lean WT (1.9 +/- 0.3 g) and ob(+/-) (2.8 +/- 0.7 g) mice. Prevention of obesity by pair feeding ob(-/-) mice dramatically reduced tumor weight (0.95 +/- 0.2 g) to a level that was significantly lower than in WT mice of the same weight. Tumor VEGF levels were the highest in the obese mouse tumors (p < 0.05), regardless of the host leptin levels. Except for the lean ob(+/-), MC4R(-/-) and ob(-/-) melanomas had the highest VEGF receptor 1 and VEGF receptor 2 protein expression (p < 0.01 and p < 0.05), respectively. These results indicate that obesity markedly increases melanoma tumor growth rate by mechanisms that may involve upregulation of VEGF pathways. Although tumor growth does not require host leptin, melanoma tumor growth may be accelerated by leptin.

90: Biological trace element research, 2010 Jun, 135(1-3)
Effect of training judo in the competition period on the plasmatic levels of leptin and pro-inflammatory cytokines in high-performance male athletes.

[Abstract]The purpose this study was to evaluate the effect of training judo in the competition period on the plasmatic levels of bioactive molecules in high-performance male athletes. The subjects were divided into two groups, a trained group with 11 judokas and a nontrained group also with 11 subjects. Blood samples obtained 60 h after training to measure plasma tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and leptin levels. The trained group presented a significant reduction in the percentage of fat and fat mass and an increase in the lumbar and lower limbs traction forces and the maximum VO(2) when compared to the nontrained group. There was no significant difference in the serum concentrations of TNF-alpha and IL-6 between the two groups. The trained group presented a lower concentration of leptin, both as absolute values as well as relative to the percentage of fat, and a higher concentration of MCP-1, in relation to the nontrained group. Our results suggest an adaptation in the capacity of synthesizing and secreting leptin in response to chronic stress in judo, what suggests a neuro-hormonal adjustment that guarantees the efficiency of metabolism. The changes of MCP-1 indicated a possible inflammatory state.

91: Proceedings. Biological sciences / The Royal Society, 2009 Nov 22, 276(1675)
Leptin increases maternal investment.

[Abstract]The primary goal of virtually all organisms is to produce genetic offspring, thereby passing on their genes to future generations. Offspring production, however, is limited by available resources within an environment. Moreover, distributing sufficient energy among competing physiological systems is challenging and can result in trade-offs between self-maintenance and offspring investment when resources are limited. In the current study, we tested the hypothesis that the adipose hormone leptin is involved in mediating energetic trade-offs between competing physiological systems. Specifically, we tested the effects of elevated maternal leptin on investment into offspring production versus self maintenance (immune function), in the Siberian hamster (Phodopus sungorus). The current study provides the first evidence that leptin serves as a signal to mothers of available energy resulting in epigenetic effects. Therefore, elevated leptin allows females to retain more embryos to parturition, and rear more offspring to weaning via reduced maternal infanticide. Innate immune response was suppressed seemingly as a result of these enlarged litters, suggesting that the observed fitness increase is not without costs to the mother. Collectively, these findings suggest that leptin plays a critical role in allowing mothers to determine how much energy to invest in the production and care of young versus self-maintenance.

92: Molecular and cellular endocrinology, 2010 Jan 15, 314(1)
Central leptin action improves skeletal muscle AKT, AMPK, and PGC1 alpha activation by hypothalamic PI3K-dependent mechanism.

[Abstract]Central leptin action requires PI3K activity to modulate glucose homeostasis and peripheral metabolism. However, the mechanism behind this phenomenon is not clearly understood. We hypothesize that hypothalamic PI3K activity is important for the modulation of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway, PGC1 alpha, and AKT in skeletal muscle (SM). To address this issue, we injected leptin into the lateral ventricle of rats. Hypothalamic JAK2 and AKT were activated by intracerebroventricular (ICV) injection of leptin in a time-dependent manner. Central leptin improved tolerance to glucose (GTT), increased PGC1 alpha expression, and AKT, AMPK, ACC and JAK2 phosphorylation in the soleus muscle. Previous ICV administration of either LY294002 or propranolol (IP) blocked these effects. We concluded that the activation of the hypothalamic PI3K pathway is important for leptin-induced AKT phosphorylation, as well as for active catabolic pathway through AMPK and PGC1 alpha in SM. Thus, a defective leptin signalling PI3K pathway in the hypothalamus may contribute to peripheral resistance to insulin associated to diet-induced obesity.

93: Journal of anatomy, 2009 Nov, 215(5)
Leptin increases growth of primary ossification centers in fetal mice.

[Abstract]The effect of peripheral leptin on fetal primary ossification centers during the early phases of bone histogenesis was investigated by administration of leptin to pregnant mice. Fourteen pregnant mice were divided into two groups. The treated pregnant group was subcutaneously injected in the intrascapular region with supraphysiologic doses (2 mg kg(-1)) of leptin (Vinci Biochem, Firenze, Italy) in a volume of 0.1 mL per 10 g body weight, at the 7th, 9th and 11th day of gestation. The control group was treated with physiological solution in the same manner and same times as the treated group. The new-born mice were killed 1 day after birth and the primary ossification centers were stained with Alizarin Red S after diaphanizing the soft tissues in 1% potassium hydroxide. The development of both endochondral and intramembranous ossification centers was morphometrically analysed in long bones. The results showed that the ossification centers of mice born by mothers treated with leptin grow more rapidly in both length and cross-sectional area compared with mice born by the untreated mothers. As the development of long bones depends on endochondral ossification occurring at proximal and distal epiphyseal plates as well as on intramembranous ossification along the periosteal surface, it appears that leptin activates the differentiation and proliferation of both chondrocytes and osteoblasts. The role of leptin as a growth factor of cartilage and bone is discussed in the light of the data reported in the literature.

94: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2009 Dec, 24(12)
Human uraemic plasma stimulates release of leptin and uptake of tumour necrosis factor-{alpha} in visceral adipocytes.

[Abstract]BACKGROUND: End-stage renal disease (ESRD) is commonly associated with anorexia, malnutrition and inflammation. In addition to serving as the primary reservoir for energy storage, adipocytes produce numerous pro- and anti-inflammatory mediators and regulate food intake by releasing the appetite-suppressing (leptin) and appetite-stimulating (adiponectin) hormones. Under normal conditions, release of leptin is stimulated by feeding to prevent excess intake, and release of adiponectin is stimulated by fasting to induce feeding. However, under certain pathological conditions such as inflammation, maladaptive release of these hormones leads to anorexia, wasting and malnutrition and simultaneously intensifies inflammation. Anorexia, malnutrition and inflammation in ESRD are frequently accompanied by hyper-leptinaemia. This study was designed to test the hypothesis that uraemic plasma may stimulate leptin release and suppress adiponectin release in normal adipocytes. METHODS: Visceral adipose tissue was harvested from normal rats, and adipocytes were isolated and incubated for 2-4 h in media containing 90% plasma from 12 ESRD patients (before and after haemodialysis) and 12 normal control subjects. RESULTS: The ESRD group had a marked elevation of plasma TNF-alpha, IL-6, IL-8 and leptin concentrations before and after haemodialysis. Incubation in media containing plasma from the ESRD group elicited a much greater leptin release by adipocytes than that containing normal plasma. Post-dialysis plasma evoked an equally intense leptin release. The rise in leptin release was coupled with a parallel fall in TNF-alpha concentration in the incubation media. In contrast to leptin, adiponectin release in the presence of uraemic plasma was similar to that found with the control plasma. CONCLUSIONS: Exposure to uraemic plasma induces exuberant release of leptin that is coupled with avid uptake of TNF-alpha by visceral adipocytes. These observations confirm the role of TNF-alpha, formerly known as cachexin, in the over-production and release of leptin in patients with ESRD.

95: Cytokine, 2009 Dec, 48(3)
Expression patterns of leptin receptor (OB-R) isoforms and direct in vitro effects of recombinant leptin on OB-R, leptin expression and cytokine secretion by human hematopoietic malignant cells.

[Abstract]Several studies have implicated leptin in the pathophysiology of neoplasias. We investigated the direct effect of leptin on malignant hematopoietic tissue that included: primary acute myeloid leukemia (AML) cells, leukemic cell lines and bone marrow biopsies from multiple myeloma (MM) patients. PBMC, T-cells, B-cells and monocytes from healthy subjects served as controls. We defined the patterns of OB-R isoform expression in AML cells and leukemic cell lines in comparison to control cells by RT-PCR. rLeptin upregulated the expression of OB-R and endogenous leptin in AML blasts and certain cell lines but not in control cells. Cytometric Bead Array analysis of pro- and anti-inflammatory cytokines showed that rleptin upregulates IL-6 secretion by AML cells, various cytokines by the leukemic cell lines tested and IL-10 secretion by control PBMC, contributed by monocytes. Western immunoblotting revealed that the effect of rleptin was independent of JAK-2/phospho-JAK-2 protein levels. Finally, MM biopsies stained positive for leptin and, to a lesser extend, OB-R. Immunoreactivity was confined mostly to the nucleus of the myeloma cells. Normal myelocytes, promyelocytes and megakaryocytes stained weakly positive, and erythroid cells were constantly negative. We propose that the leptin/OB-R system is strongly and directly involved in supporting the growth of hematopoietic malignancies.

96: Journal of cellular physiology, 2009 Nov, 221(2)
Leptin attenuates hypoxia/reoxygenation-induced activation of the intrinsic pathway of apoptosis in rat H9c2 cells.

[Abstract]Cardiomyocyte apoptosis is a component of cardiac remodeling that can contribute to heart failure in obesity. A role for leptin in mediating this process has been suggested and the objective of this work was to investigate the effect of leptin on apoptosis and associated mechanisms in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic myocardial ischemia/reperfusion. Qualitative immunofluorescent and quantitative laser scanning cytometry approaches demonstrated that exposure of cells to HR increased DNA fragmentation (TUNEL staining) which was attenuated by leptin (6 nM, 1 h) pretreatment. We also found increased annexin-V binding and caspase-3 activity in cells exposed to HR, both of which were attenuated by leptin pretreatment. Leptin reduced HR-induced translocation of the pro-apoptotic protein Bax to the mitochondrial membrane, which provides a mechanism to explain its protective effect. Consequently, leptin attenuated the HR-induced decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria. Leptin treatment increased the phosphorylation of p38 MAPK and AMPK and respective inhibitors of these kinases, SB203580 and Compound C, prevented the ability of leptin to decrease HR-induced caspase-3 activity. In conclusion, we establish mechanisms via which leptin exerts anti-apoptotic effects that may be of significance in understanding the development of heart failure in obesity.

97: Brain research, 2009 Oct 27, 1295(19)
Leptin "gates" thermogenic action of thyrotropin-releasing hormone in the hindbrain.

[Abstract]Leptin, acting as a measure of metabolic fuel availability, exerts a powerful permissive influence on neurogenic thermogenesis. During starvation and an absence of leptin, animals cannot produce thermogenic reactions to cold stress. However, thermogenesis is rescued by restoring leptin. We have previously observed (Hermann, G.E., Barnes, M.J., Rogers, R.C., 2006. Leptin and thyrotropin-releasing hormone: cooperative action in the hindbrain to activate brown adipose thermogenesis. Brain Res. 1117, 118-124.) a highly cooperative interaction between leptin and thyrotropin-releasing hormone [TRH] to activate hindbrain generated thermogenic responses. Specifically, exposure to both leptin and TRH elicited a 3.5 degrees C increase in brown adipose tissue [BAT] thermogenesis, while leptin alone did not evoke any change, and TRH alone caused only approximately 1 degrees C increase. The present study shows that the leptin-TRH synergy in controlling brown adipose [BAT] thermogenesis is order-specific and dependent on the feeding status of the animal. That is, fourth ventricular [4V] application of leptin to the food-deprived animal, before TRH injection, yields a substantial increase in BAT; while the reverse order yields a significantly smaller effect. If the animal were fed within minutes of anesthesia, then exogenous leptin was not necessary for TRH to yield a large increase in BAT temperature. The leptin-TRH synergy was uncoupled by pretreatment with the phosphoinositol-tris phosphate kinase [PI3K] inhibitor, wortmannin and the Src-SH2 antagonist, PP2. The TRH transduction mechanism utilizes phospholipase C [PLC] potently regulated by the SH2 site. Previous work in culture systems suggests that the product of PI3K activity [PIP3] potently upregulates PLC by activating the SH2 domain of the PLC complex. Perhaps leptin "gates" the thermogenic action of TRH in the hindbrain by invoking this same mechanism.

98: Regulatory peptides, 2009 Nov 27, 158(1-3)
Influence of long-term growth hormone replacement on leptin and ghrelin in GH deficiency before and after glucose load.

[Abstract]INTRODUCTION: This cross-sectional study was performed to evaluate the effect of long-term GH substitution on leptin and ghrelin in GH deficiency (GHD). METHODS: Leptin and ghrelin were measured after glucose load for 3 h in 52 pat and 10 age- and BMI-matched healthy controls. 22 GHD pat were on GH substitution (GH-Sub) for a median of 10 yr (range 2-27 yr). 30 age- and BMI-matched GHD pat were not substituted for at least 2 yr (non-Sub). RESULTS: Basal leptin (8 microg/l (1-130) vs. 16 microg/l (3-89), p<0.05) and AUC of leptin (p<0.05) was significantly lower in GH-Sub compared to non-Sub. In the control group, leptin was higher compared to GH-Sub and similar to non-Sub (19 microg/l (4-57)). Ghrelin (baseline: non-Sub 113 ng/l (61-270), GH-Sub 145 ng/l (83-280), controls 131 ng/l (83-274)) were slightly but not significantly lower for non-Sub. After glucose load, a significant decrease in leptin appeared in both GHD groups, but not in the control group. Ghrelin decreased significantly in all groups. CONCLUSION: Lipolytic GH causes lower leptin in GH-Sub. The reason for similar ghrelin might be the compensating effect of acute GH suppression and stimulating low fat mass on ghrelin. Leptin regulation after glucose load is impaired in GHD, whereas ghrelin regulation seems to be not effected.

99: Recent patents on inflammation & allergy drug discovery, 2009 Nov 1, 87(14)
Leptin as Clinical Target.

[Abstract]PLeptin is an adipocyte-derived hormone with pleiotropic effects on energy homeostasis, endocrine and reproductive functions, and immune responses. The multiple actions of leptin have led to the design and development of several leptin-based approaches to modulate the metabolic and endocrine status, to reduce inflammation, and to improve immune responses. Here we review the current patents on leptin in different clinic applications.

100: Animal reproduction science, 2010 Jan, 117(1-2)
Relation between leptin and estradiol levels in Egyptian lactating Arab mares during foaling heat.

[Abstract]Sixteen Arab lactating mares belonging to Al-Zahraa Arab Horse Stud underwent two ultrasound examinations at 3 weeks interval starting from the day of demonstration of foaling heat. In addition, daily blood samples were collected from parturition until after exhibiting first postpartum estrus (day 11) with daily observation of estrous signs. Both leptin and estradiol hormones were assayed. Mean day of foaling heat was 8.9+/-0.9 day. Most mares came in foaling heat during days 9 and 10 had high conception rate compared to those who came in estrus earlier or later. Estradiol levels were high after day of foaling then decrease after expression of foaling heat. But leptin levels increase from day 8 to day 10 compared to other days before and after the first ovulation. A significant positive correlation was found between estradiol and leptin (r=0.58, p<0.025). The positive correlation between leptin and estradiol led us to suggest that leptin hormone plays an important role in ovulation of the first postpartum estrus in mares.

101: European journal of haematology, 2009 Nov, 83(5)
Abnormal adipokine levels and leptin-induced changes in gene expression profiles in multiple myeloma.

[Abstract]BACKGROUND: Studies have revealed an association between overweight/obesity and multiple myeloma. However, the factors linking a dysregulated energy metabolism to this disease have not been identified. Adipose tissue produces and secretes the adipokines leptin, adiponectin and resistin, involved in metabolism and cell growth. METHODS: We measured the plasma concentrations of these three adipokines in newly diagnosed multiple myeloma as well as in patients with relapse. We further explored the importance of leptin in multiple myeloma by performing gene expression profiling in two myeloma cell lines. RESULTS: At diagnosis, leptin was increased (P < 0.05) in both female and male patients compared with controls. Adiponectin was reduced (P < 0.05) among male patients, whereas no significant changes in resistin were noted among any patients. In patients with relapse and treated with thalidomide, no particular adipokine pattern was revealed. Leptin induced the expression of several genes important for cell signaling, growth and viability. CONCLUSIONS: The plasma concentrations of leptin and adiponectin, but not resistin, were abnormal in newly diagnosed multiple myeloma. Adipose tissue may modify the growth and metabolism of myeloma cells through adipokine-mediated effects.

102: The Journal of investigative dermatology, 2009 Nov, 129(11)
Nestin in human skin: exclusive expression in intramesenchymal skin compartments and regulation by leptin.

[Abstract]Cutaneous nestin+ cells are of substantial interest in regenerative medicine. However, the location of nestin+ cells in situ remains controversial. We therefore sought to determine their location in female human scalp skin, using stringently controlled immunohistochemical techniques, Western blot analysis, and in situ hybridization and complementing those techniques with relative and quantitative reverse transcriptase-PCR of enzymatically digested or laser-capture microdissected human hair follicle (HF) compartments. We show here that the immunoreactivity (IR) patterns obtained with anti-nestin antibodies are highly dependent on the tissue-fixation and immunohistochemical methods used. NESTIN mRNA could not be detected within HF-associated epithelial cells in situ or in RNA extracts of the microdissected HF epithelium. Instead, NESTIN transcripts were found only in intramesenchymal skin compartments. Individual cells showing both, specific nestin IR and NESTIN mRNA were detectable in the connective-tissue sheaths of human HFs, sebaceous and sweat glands. Moreover, stimulation of organ-cultured human scalp skin with the adipokine leptin increased the number of nestin+ cells in these intramesenchymal skin locations, whereas no specific nestin IR could be induced by leptin within the HF epithelium, including the bulge. Therefore, nestin expression at the gene and protein levels in human scalp skin is restricted to the periappendage mesenchyme and can be stimulated by leptin.

103: General and comparative endocrinology, 2010 Jan 1, 165(1)
Leptin and ghrelin in anadromous Arctic charr: Cloning and change in expressions during a seasonal feeding cycle.

[Abstract]Anadromous (sea-migrating) Arctic charr (Salvelinus alpinus) display pronounced seasonal variations in food intake and growth and is an interesting model for studying mechanisms of appetite regulation. In this study cDNAs encoding for ghrelin (GHRL) and leptin (LEP) in Arctic charr were cloned, after which stomach GHRL and liver LEP mRNA expressions were examined by qPCR during a seasonal feeding cycle of semi-wild anadromous Arctic charr. The fish were captured as they returned from summer feeding in seawater and transferred to an indoor tank where they were fed in excess until October the year after. Growth rate was low in late winter, increased in late spring and reached a peak during summer, and then declined during autumn, when the fish became sexually mature. The changes in growth rate were associated with corresponding changes in the proportion of fish that had been eating at each sampling date, and whole body lipid status. Stomach GHRL mRNA expression was high in late winter, decreased to a nadir in mid-summer and increased again to a high level in early autumn. Liver LEP mRNA remained low during winter, spring and early summer, after which there was a gradual, 7-fold increase until October. The seasonal changes in ghrelin and leptin support a role of these hormones in the long-term regulation of energy homeostasis in the anadromous Arctic charr. It cannot be excluded, however, that the increase in liver leptin expression during autumn is related to sexual maturation.

104: Journal of neuroscience research, 2009 Nov 1, 87(14)
Cytokines decrease expression of interleukin-6 signal transducer and leptin receptor in central nervous system glia.

[Abstract]Multiple sclerosis (MS) lesion formation is modulated by cytokines secreted within the central nervous system (CNS). Th1 lymphocytes and monocyte/macrophages (MM) likely induce lesion formation, whereas Th2 lymphocytes may inhibit formation. To explore the role of cytokines in MS lesions, we used gene arrays to investigate effects of cytokines representative of Th1 and Th2 cells and M/M on gene expression in cultured CNS glia; at 6 hr, all three increased expression of the interleukin-6 (IL-6) gene and decreased expression of the leptin receptor gene (obr), which mediates IL-6 production and other inflammatory responses. However, expression of a closely related gene, the interleukin-6 signal transducer or gp130 (IL-6st), showed no changes at 6 hr. IL-6st is an essential component of receptor complexes for IL-6 and other cytokines and growth factors that play critical roles in CNS inflammation, protection, and/or regeneration. To analyze expression of IL-6st and leptin receptor over time, we incubated rat CNS glial cultures for 6 hr to 5 days with the cytokines. All three cytokine mixtures down-regulated both IL-6st and leptin receptor mRNA and protein for up to 5 days. Immunocytochemical staining showed expression of both IL-6st and leptin receptor in all three types of glia, with lower IL-6st expression by 3 days. Down-regulation of IL-6st and leptin receptor in glia by cytokines could lead to decreased signaling by the proinflammatory IL-6 and reduced responses to regenerative/protective growth factors such as leukemia inhibitory factor and ciliary neurotrophic factor, potentially affecting the disease course in MS.

105: Fertility and sterility, 2010 Aug, 94(3)
Serum leptin levels, hormone levels, and hot flashes in midlife women.

[Abstract]OBJECTIVE: To examine the associations between serum leptin levels, sex steroid hormone levels, and hot flashes in normal weight and obese midlife women. DESIGN: Cross-sectional study. SETTING: University clinic. PATIENT(S): 201 Caucasian, nonsmoking women aged 45 to 54 years with a body mass index of <25 kg/m(2) or >/=30 kg/m(2). INTERVENTION(S): Questionnaire, fasting blood samples. MAIN OUTCOME MEASURE(S): Serum leptin and sex steroid hormone levels. RESULT(S): Correlation and regression models were performed to examine associations between leptin levels, hormone levels, and hot flashes. Leptin levels were associated with BMI, with "ever experiencing hot flashes" (questionnaire), with hot flashes within the last 30 days, and with duration of hot flashes (>1 year, P=.03). Leptin was positively correlated with testosterone, free testosterone index, and free estrogen index and inversely associated with levels of sex hormone-binding globulin. In women with a body mass index >/=30 kg/m(2), leptin levels no longer correlated with testosterone levels. CONCLUSION(S): Serum leptin levels are associated with the occurrence and duration of hot flashes in midlife women; however, no correlation was found between leptin and serum estradiol.

106: Acta diabetologica, 2010 Jun, 47(2)
Visceral adiposity and leptin are independently associated with C-reactive protein in Korean type 2 diabetic patients.

[Abstract]The inflammatory marker, C-reactive protein (CRP) is associated with long-term cardiovascular events. The aim of the study was to investigate the factors contributing to serum CRP, assess the relationship between CRP level and the parameters of visceral obesity, and examine the association between leptin and CRP level in type 2 diabetic patients. 150 patients with type 2 diabetes were enrolled. These patients were recently diagnosed (< or =3 years) with type 2 diabetes and were drug naive or taking sulfonylureas only. BMI, WC, and serum concentration of CRP, glycosylated hemoglobin (HbA1c), glucose, lipids, plasminogen activator-1 (PAI-1) and leptin were measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). We measured the carotid intima-media thickness (IMT). Fat mass assessed by dual-energy X-ray absorptionmetry and abdominal fat distribution was determined by CT scan. Serum concentration of CRP was significantly correlated with BMI (gamma = 0.257, P < 0.01), WC (gamma = 0.293, P < 0.01), fat mass (gamma = 0.213, P < 0.01), total adipose tissue (gamma = 0.263, P < 0.01), visceral adipose tissue (gamma = 0.296, P < 0.01), insulin (gamma = 0.189, P = 0.047), PAI-1 (gamma = 0.206, P < 0.01), leptin (gamma = 0.322, P < 0.01), mean IMT (gamma = 0.132, P = 0.042), and HOMA-IR (gamma = 0.172, P = 0.045). After adjustment for age and gender, multiple regression analysis showed that serum CRP was significantly associated with leptin (beta = 0.326, P = 0.01) and visceral adipose tissue (beta = 0.265, P = 0.035). In conclusion, serum CRP level is significantly associated with obesity, especially the visceral adipose tissue, and serum leptin is another important independent factor associated with CRP in Korean type 2 diabetic patients.

107: Obesity (Silver Spring, Md.), 2009 Nov, 17(11)
Fat and water (1)h MRI to investigate effects of leptin in obese mice.

[Abstract]Leptin is known to be associated with regulation of body weight and fat content. The effects of exogenous leptin on abdominal visceral (VS) and subcutaneous (SC) fat volume and hepatic fat-to-water ratio in leptin-deficient obese mice were investigated by (1)H magnetic resonance imaging (MRI). Chemical shift-selected fat and water (1)H MRI of control and leptin-treated mice were obtained 1 day before treatment and after 7 days of treatment (0.3 mg/kg/day). Hepatic fat-to-water ratio and VS fat volume decreased significantly with treatment, whereas SC fat volume did not change. Noninvasive measurement of fat and water content in different body regions using MRI should prove useful for evaluating new drugs for the treatment of obesity and other metabolic disorders.

108: Obesity (Silver Spring, Md.), 2009 Feb 26,
Plasma MR-proADM Correlates to BMI and Decreases in Relation to Leptin After Gastric Bypass Surgery.

[Abstract]Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR-proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m(2) and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux-en-Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR-proADM, cortisol, leptin, C-reactive protein (CRP) thyroid-stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR-proADM levels (r = 0.714, P < 0.001), also after adjustment for age and gender (r = 0.767, P < 0.001). In obese subjects, there was a positive relationship between MR-proADM and leptin (r = 0.511, P = 0.006). Following RYGB, plasma MR-proADM decreased from 0.76 +/- 0.03 to 0.62 +/- 0.02 pg/ml (P < 0.0001). RYGB-induced changes in MR-proADM correlated significantly to changes in leptin (r = 0.533, P = 0.004) and in CRP (r = 0.429, P = 0.023). We conclude that BMI is an independent predictor of circulating MR-proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR-proADM, which is related to surgery-induced changes in both circulating leptin and systemic inflammation.Obesity (2009) doi:10.1038/oby.2009.22.

109: Journal of endocrinological investigation, 2008 Dec, 31(12)
Growth hormone/insulin-like growth factor I axis, glucose metabolism, and lypolisis but not leptin show some degree of refractoriness to short-term fasting in acromegaly.

[Abstract]Starvation exerts critical influence on somatotroph and leptin secretion. Fasting enhances GH levels in normal subjects, but not in GH hyposecretory states, while it always inhibits leptin secretion. We aimed to clarify the GH/IGF-I and metabolic response to short-term fasting in a GH hypersecretory state such as acromegaly. To this goal, in 8 active acromegalic (ACRO) and in 7 normal women (NS) we evaluated mean GH (mGHc), leptin (mLEPc), insulin (mINSc), glucose (mGLUc) concentrations as well as IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and free fatty acid (FFA) levels before and after 36-h fasting. Before fasting, mGHc, IGF-I, mINSc, mGLUc, and FFA levels in ACRO were higher (p<0.01) than in NS. IGFBP-3, IGFBP-1, and mLEPc were similar in ACRO and in NS. Fasting clearly (p<0.02) increased mGHc in NS only. After 36-h fasting, significant IGF-I reduction was recorded in NS only (p<0.03). IGFBP-3 did not change both in ACRO and NS. IGFBP-1 significantly increased (p<0.05) after fasting in both groups but in ACRO were lower (p<0.03) than in NS. Fasting decreased (p<0.03) mLEPc, mGLUc, and mINSc in ACRO as well as in NS; mINSc and mGLUc after fasting in ACRO persisted higher (p<0.005) than in NS. FFA levels were increased by fasting in NS (p<0.02), but not in ACRO. This study shows that GH/IGF-I axis, glucose metabolism, and lypolisis but not leptin display some degree of refractoriness to short-term fasting in acromegaly. The lack of any GH response to fasting in acromegaly would likely reflect neuroendocrine alterations secondary to the GH hypersecretory state. On the other hand, the lack of somatotropic response and the peculiarly blunted metabolic reaction to short-term fasting would partially reflect the delayed adaptation of insulin resistance to starvation.

110: The Indian journal of medical research, 2008 Dec, 128(6)
Leptin response in patients with tuberculous pleuritis.

[Abstract]BACKGROUND & OBJECTIVES: Tuberculous pleuritis is used as a model to understand the protective immune response in tuberculosis. It is predominated by Th1 response at the site of infection, where a possible role for the leptin, a known enhancer of Th1 response, could be speculated. Hence, we investigated leptin levels in pleural effusions in patients with both tuberculous (TP) and non-tuberculous (NTP) pleural effusion. METHODS: Leptin and cytokine levels were assessed in serum and pleural fluid of TP and NTP patients (N = 20 each) by ELISA. Multivariate regression analysis were performed to find the possible determinants of leptin taking leptin as the dependent and body mass index (BMI), gender, source of leptin [i.e., serum or pleural fluid (PF)], age and disease status as independent variables. RESULTS: PF leptin levels were significantly higher than serum leptin levels in both the groups however the PF leptin levels were significantly lower in TP subjects compared to NTP. The results showed that the leptin was found to be dependent on BMI but not on the other parameters. However, regression analysis based on the source of leptin showed males to be a better predictor of leptin. No correlation was observed between leptin and measured immune parameters. INTERPRETATION & CONCLUSION: Our findings demonstrated that the decreased leptin levels were associated with reduction in BMI but not with the disease status in tuberculous pleuritis.

111: The Indian journal of medical research, 2008 Dec, 128(6)
Does leptin have a role in immunity to tuberculosis?

[Abstract]BACKGROUND & OBJECTIVES: Tuberculous pleuritis is used as a model to understand the protective immune response in tuberculosis. It is predominated by Th1 response at the site of infection, where a possible role for the leptin, a known enhancer of Th1 response, could be speculated. Hence, we investigated leptin levels in pleural effusions in patients with both tuberculous (TP) and non-tuberculous (NTP) pleural effusion. METHODS: Leptin and cytokine levels were assessed in serum and pleural fluid of TP and NTP patients (N = 20 each) by ELISA. Multivariate regression analysis were performed to find the possible determinants of leptin taking leptin as the dependent and body mass index (BMI), gender, source of leptin [i.e., serum or pleural fluid (PF)], age and disease status as independent variables. RESULTS: PF leptin levels were significantly higher than serum leptin levels in both the groups however the PF leptin levels were significantly lower in TP subjects compared to NTP. The results showed that the leptin was found to be dependent on BMI but not on the other parameters. However, regression analysis based on the source of leptin showed males to be a better predictor of leptin. No correlation was observed between leptin and measured immune parameters. INTERPRETATION & CONCLUSION: Our findings demonstrated that the decreased leptin levels were associated with reduction in BMI but not with the disease status in tuberculous pleuritis.

112: Diabetes, 2009 Mar, 58(3)
Signal transduction pathways for leptin: an embarrassment of riches.

[Abstract]BACKGROUND & OBJECTIVES: Tuberculous pleuritis is used as a model to understand the protective immune response in tuberculosis. It is predominated by Th1 response at the site of infection, where a possible role for the leptin, a known enhancer of Th1 response, could be speculated. Hence, we investigated leptin levels in pleural effusions in patients with both tuberculous (TP) and non-tuberculous (NTP) pleural effusion. METHODS: Leptin and cytokine levels were assessed in serum and pleural fluid of TP and NTP patients (N = 20 each) by ELISA. Multivariate regression analysis were performed to find the possible determinants of leptin taking leptin as the dependent and body mass index (BMI), gender, source of leptin [i.e., serum or pleural fluid (PF)], age and disease status as independent variables. RESULTS: PF leptin levels were significantly higher than serum leptin levels in both the groups however the PF leptin levels were significantly lower in TP subjects compared to NTP. The results showed that the leptin was found to be dependent on BMI but not on the other parameters. However, regression analysis based on the source of leptin showed males to be a better predictor of leptin. No correlation was observed between leptin and measured immune parameters. INTERPRETATION & CONCLUSION: Our findings demonstrated that the decreased leptin levels were associated with reduction in BMI but not with the disease status in tuberculous pleuritis.

113: Molecular human reproduction, 2009 Feb 26, 58(3)
Insulin and leptin receptors as possible new candidates for endocrine control in normal and disturbed human pregnancy.

[Abstract]Leptin and Insulin are secreted into the maternal and to a lesser extent into the fetal blood stream where they act as placental signals and nourish the fetus, making them possible candidates for the endocrine control of the placenta. We investigated differences in Leptin (LR) and Insulin receptor (IR) expression in normal and disturbed first trimester human pregnancy at protein level by immunohistochemistry and at mRNA level by real time RT-PCR (TaqMan). Highest expression of LR and IR was present in villous (VT) and extravillous trophoblasts (EVT). In hydatidiform mole trophoblasts, significantly higher LR and IR expression was observed as compared to normal pregnancy. Additionally, LR and IR were also expressed in glandular epithelial cells of the decidua, again to the highest extent in hydatidiform mole as compared to normal pregnancy. With regard to abortive placentas, significant differences were also present as compared to normal first trimester placenta in the expression of LR and IR in VT, EVT and in glandular epithelial cells of the decidua. Results at protein expression of LR and IR were confirmed at mRNA level. The majority of IR and LR are expressed on structures that are currently assumed to drive placental growth. LR and IR are strongly up-regulated in placentas of hydatidiform mole and abortion. Our findings may suggest IR and LR as possible new candidates for the endocrine control of human pregnancy.

114: British journal of sports medicine, 2010 Jul, 44(9)
Review on leptin and adiponectin responses and adaptations to acute and chronic exercise.

[Abstract]Leptin and adiponectin represent two newly discovered adipose tissue derived hormones; that are both associated with health status and glucose and free fatty acid (FFA) metabolism. Moreover, acute and chronic exercises affect body composition, carbohydrate and lipid metabolism. It is thus interesting to evaluate the effects of physical exercise and training on leptin and adiponectin levels. It seems that leptin concentration is not modified after short-term exercise (<60 min) or exercise that generates an energy expenditure lower than 800 kcal. Leptin levels decrease after long-term exercise (> or =60 min) stimulating FFA release, or after exercise that generates energy expenditure higher than 800 kcal. Adiponectin concentration presents a delayed increase (30 min) after short-term intense exercise (<60 min) performed by trained athletes. For adiponectin, limited data suggest that adiponectin concentration presents a delayed increase (30 min) after short-term intense exercise (<60 min) performed by trained athletes. It seems that adiponectin concentrations do not change in response to long-term exercise (> or =60 min). Short-term training (<12 weeks) and long-term training (> or =12 weeks) show contrasting results regarding leptin and adiponectin. Most training studies which improve fitness levels and affect body composition could decrease leptin and increase adiponectin concentrations.


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