Human Leptin Research Articles

Acquired partial lipoatrophy as graft-versus-host disease and treatment with metreleptin: two case reports

IntroductionAcquired partial lipoatrophy has been reported after bone marrow transplantation during childhood; however, no adult cases have previously been reported. We herein report two adult cases of acquired partial lipoatrophy after transplantation.Case presentationA 28-year-old Japanese woman developed diabetic ketoacidosis and received insulin therapy after bone marrow transplantation. She manifested partial lipoatrophy of the extremities, prominent insulin resistance, hyperglycemia, hypertriglyceridemia, and fatty liver. A 40-year-old Japanese woman underwent liver transplantation from a living donor for alcoholic liver disease after abstinence from alcohol. She newly developed non-alcoholic steatohepatitis and diabetes. Non-alcoholic steatohepatitis progressed to liver failure, and a second liver transplantation from a brain-dead donor was performed at 42 years of age. She demonstrated loss of subdermal fat of the upper and lower extremities, prominent insulin resistance, hyperglycemia, and hypertriglyceridemia. In both cases, the injection of recombinant methionyl human leptin reversed all of the metabolic abnormalities.ConclusionsAcquired partial lipoatrophy after transplantation is a manifestation of chronic graft-versus-host disease in adults. This entity is associated with diabetes with prominent insulin resistance and severe hypertriglycemia and can be successfully treated with metreleptin for the long term.

Leptin stimulates DMP-1 and DSPP expression in human dental pulp via MAPK 1/3 and PI3K signaling pathways

IntroductionTo investigate the physiological function of leptin in human dental pulp, and to determine the specific pathways implicated in its effect. MethodsTwenty-seven dental pulp samples were obtained from human third molars. Pulp samples were treated with or without human recombinant leptin. Leptin functional effect was analyzed in terms of regulation of the synthesis levels of DSPP and DMP-1, determined by immunoblot. ResultsLeptin stimulated DMP-1 and DSPP synthesis in all human dental pulp specimens. The stimulatory effect of leptin on DMP-1 and DSPP synthesis was partially prevented by blocking mitogen-activated protein kinase (MAPK 1/3) and phosphatidylinositol 3 kinase (PI3K) pathways, respectively. ConclusionsThe present study demonstrates the functional effect of leptin in human dental pulp stimulating the expression of DMP-1 and DSPP, both proteins implicated in dentinogenesis. Leptin stimulates DSPP expression via PI3K pathway and DMP-1 synthesis via MAPK 1/3 pathway. These results support the role of leptin in pulpal reparative response, opening a new research line that could have translational application to the clinic in vital pulp therapy procedures.

Update on Therapeutic Options in Lipodystrophy.

The purpose of this review is to summarize the therapeutic approach for lipodystrophy syndromes with conventional treatment options and metreleptin therapy in detail and to point out the current investigational treatments in development. The observation of leptin deficiency in patients with lipodystrophy and the potential of leptin replacement to rescue metabolic abnormalities in animal models of lipodystrophy were followed by the first clinical study of leptin therapy in patients with severe lipodystrophy. This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy. These studies ultimately led to the recent FDA approval of metreleptin for the treatment of generalized lipodystrophy and EMA approval for both generalized and partial lipodystrophy. Additional research efforts in progress focus on novel treatment options, predominantly for patients with partial lipodystrophy. Current treatment of generalized lipodystrophy includes metreleptin replacement as an adjunct to diet and standard treatment approach for metabolic consequences of lipodystrophy. Beyond metreleptin, a number of different compounds and treatment modalities are being studied for the treatment of partial lipodystrophy.

Leptin impairs the therapeutic effect of ionizing radiation in oral squamous cell carcinoma cells.

Leptin, an important hormone controlling energy homeostasis, has been linked to the pathogenesis of oral squamous cell carcinoma (OSCC). Evidence indicates that head and neck cancer patients undergoing radiotherapy show decreased leptin levels after radiotherapy treatment. Thus, we investigated, through phenotypic and molecular analyses, whether leptin can compromise the therapeutic effect of ionizing radiation and neoplastic behavior of OSCC cells. The human OSCC-derived cell lines SCC9 and SCC4 were treated with human recombinant leptin and exposed to 6Gy of irradiation. We performed the invitro assays of cell migration, death, proliferation, and colony-forming ability. The reactive oxygen species (ROS) levels and proteome analysis by mass spectrometry were also conducted. Leptin was able to increase cell proliferation, migration, and colony-forming ability, despite the suppressive effect induced by irradiation. Furthermore, the leptin promoted a significant reduction of ROS intracellular accumulation, and increased expression of the cancer-related proteins, as ACTC1, KRT6A, and EEF2 in irradiated OSCC cells. Our findings suggest that leptin impairs responsivity of OSCC cells to the ionizing radiation, reducing the suppressive effects of irradiation on the neoplastic phenotype, and increasing protein expression critical to carcinogenesis.

Functional and Phenotypic Characteristics of Human Leptin Receptor Mutations.

Several case series of extreme early-onset obesity due to mutations in the human leptin receptor (LEPR) gene have been reported. In this review we summarize published functional and phenotypic data on mutations in the human LEPR gene causing severe early-onset obesity. Additionally, we included data on six new cases from our obesity center. Literature research was performed using PubMed and OMIM. Functional relevance of mutations was estimated based on reported functional analysis, mutation size, and location, as well as phenotypic characteristics of affected patients. We identified 57 cases with 38 distinct LEPR mutations. We found severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism as cardinal features of a complete loss of LEPR function. Other features, for example, metabolic disorders and recurring infections, were variable in manifestation. Obesity degree or other manifestations did not aggregate by genotype. Few patients underwent bariatric surgery with variable success. Most mutations occurred in the fibronectin III and cytokine receptor homology II domains, whereas none was found in cytoplasmic domain. In silico data were available for 25 mutations and in vitro data were available for four mutations, revealing residual activity in one case. By assessing provided information on the clinical phenotype, functional analysis, and character of the 38 mutations, we assume residual LEPR activity for five additional mutations. Functional in vitro analysis is necessary to confirm this assumption.

Effects of Leptin on the Skeleton.

Leptin originates in adipocytes, including those in bone marrow, and circulates in concentrations 20 to 90 times higher than those in the cerebrospinal fluid. It has direct anabolic effects on osteoblasts and chondrocytes, but it also influences bone indirectly, via the hypothalamus and sympathetic nervous system, via changes in body weight, and via effects on the production of other hormones (e.g., pituitary). Leptin's role in bone physiology is determined by the balance of these conflicting effects. Reflecting this inconsistency, the leptin-deficient mouse has reduced length and bone mineral content of long bones but increased vertebral trabecular bone. A consistent bone phenotype in human leptin deficiency has not been established. Systemic leptin administration in animals and humans usually exerts a positive effect on bone mass, and leptin administration into the cerebral ventricles usually normalizes the bone phenotype in leptin-deficient mice. Reflecting the role of the sympathetic nervous system in mediating the central catabolic effects of leptin on the skeleton, β-adrenergic agonists and antagonists have major effects on bone in mice, but this is not consistently seen in humans. The balance of the central and peripheral effects of leptin on bone remains an area of substantial controversy and might vary between species and according to other factors such as body weight, baseline circulating leptin levels, and the presence of specific pathologies. In humans, leptin is likely to contribute to the positive relationship observed between adiposity and bone density, which allows the skeleton to respond appropriately to changes in soft tissue mass.

Human Milk Adiponectin and Leptin and Infant Body Composition over the First 12 Months of Lactation.

Human milk (HM) adipokines may influence infant feeding patterns, appetite regulation, and body composition (BC). The associations between concentrations/calculated daily intakes (CDI) of HM adipokines in the first 12 months postpartum and maternal/term infant BC, and infant breastfeeding parameters were investigated. BC of breastfeeding dyads (n = 20) was measured at 2, 5, 9, and/or 12 months postpartum with ultrasound skinfolds (infants) and bioimpedance spectroscopy (infants/mothers). 24-h milk intake and feeding frequency were measured along with whole milk adiponectin and skim and whole milk leptin (SML and WML) and CDI were calculated. Statistical analysis used linear regression/mixed effects models; results were adjusted for multiple comparisons. Adipokine concentrations did not associate with infant BC. Higher CDI of adiponectin were associated with lower infant fat-free mass (FFM; p = 0.005) and FFM index (FFMI; p = 0.009) and higher fat mass (FM; p < 0.001), FM index (FMI; p < 0.001), and %FM (p < 0.001). Higher CDI of SML were associated with higher infant FM (p < 0.001), FMI (p < 0.001), and %FM (p = 0.002). At 12 months, higher CDI of WML were associated with larger increases in infant adiposity (2–12 month: FM, p = 0.0006; %FM, p = 0.0004); higher CDI of SML were associated with a larger decrease in FFMI (5–12 months: p = 0.0004). Intakes of HM adipokines differentially influence development of infant BC in the first year of life, which is a critical window of infant programming and may potentially influence risk of later disease via modulation of BC.

Obesity and Breast Cancer: Association of Serum Adiponectin, Leptin, and Adiponectin–Leptin Ratio as Risk Biomarkers

AbstractIntroduction: Obesity has been associated with the development of breast cancer. The objectives were to study the association of serum adiponectin, serum leptin, and adiponectin–leptin ratio (ALR) in patients with breast cancer and matched controls, and to study their relationship with the various clinicopathological characteristics of breast cancer. Materials and Methods: A prospective, hospital-based case–control study was conducted on 40 patients with a first-confirmed histopathology diagnosis of breast cancer and 40 controls comprising individuals without a history of cancer simultaneously recruited from the health examination clinics during the same study period. Serum adiponectin and leptin concentrations were measured in a single run using commercially available kits (Human ADP/Acrp30 [adiponectin] enzyme-linked immune-sorbent assay [ELISA] kit and Human Leptin ELISA kit, Elabscience Biotechnology Co., Ltd) according to the manufacturer's instructions. Results:: Serum adiponectin levels were reduced significantly in breast cancer patients, in comparison to controls (P = 0.04), while serum leptin levels were increased significantly in breast cancer patients, in comparison to controls (P = 0.03). ALR was significantly lower in breast cancer cases, in comparison to controls (P = 0.05). There was no correlation between receptor status (estrogen receptor, progesterone receptor, Her2/neu), aggressiveness of disease in terms of tumor size, nodal metastases, stage, tumor grade, and serum adiponectin levels, leptin levels, or ALR. Body mass index was negatively correlated with serum adiponectin levels and ALR (r = 0.33, P = 0.03; r = 0.39, P = 0.01, respectively) and positively correlated with serum leptin levels (r = 0.34, P = 0.02). Conclusion: In summary, our results suggest that low serum adiponectin levels, ALR, and high serum leptin levels are associated with breast cancer.

Preparation of Potent Leptin Receptor Antagonists and Their Therapeutic Use in Mouse Models of Uremic Cachexia and Kidney Fibrosis.

Leptin antagonists (L39A/D40A/F4lA mutants) of mouse, human, rat and ovine leptins were developed in our laboratory by rational mutagenesis, expressed in Escherichia coli, refolded and purified to homogeneity. Pegylation of these antagonists resulted in long-acting reagents suitable for in-vivo studies. Further selection of high-affinity leptin antagonists was achieved by random mutagenesis of the whole open reading frame followed by yeast- surface display; an additional mutation (D23L) increased their affinity toward leptin receptor 60-fold. This superactive pegylated mouse leptin antagonist (PLA) exhibited a strong orexigenic effect, leading, in 10-14 days, to a 40% increase in body weight resulting mainly from obesity; this was reversed once PLA treatment was ceased. Cachexia is common in patients with Chronic Kidney Disease (CKD). Our studies suggested that leptin mediates cachexia by decreasing food intake while increasing energy consumption in CKD mice. We showed that PLA ameliorates CKD-associated cachexia in mice. Leptin may also contribute to the development of muscle and renal fibrosis in CKD, serious complications associated with increased morbidity and mortality. Transforming growth factor (TGF)-β signaling may be the most potent mediator of fibrogenesis in multiple organs, and leptin is a co-activator of TGF-β. Muscle fibrosis was evident in our CKD mice and PLA treatment significantly reduced the mRNA levels of TGF- β1 and its downstream targets in their muscle and renal tissues. PLA may offer a novel therapeutic strategy for CKD-associated cachexia, muscle and renal fibrosis to improve CKD patients' survival and quality of life.

Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis.

The ongoing chronic inflammation and subsequent fibrosis play an important role in ligamentum flavum (LF) fibrosis and hypertrophy in patients with lumbar spinal canal stenosis (LSCS). Leptin is a chronic inflammatory mediator and involved in the fibrotic process in multiple organ systems. The present study aimed to investigate the role of leptin in LF fibrosis and its related regulatory mechanisms. The LF specimens were obtained during the surgery from 12 patients with LSCS (LSCS group) and 12 control patients with lumbar disc herniation (LDH) group. The morphologic changes and fibrosis score of LF were assessed by Hematoxylin and eosin (H&E) and Masson’s trichrome staining respectively. The location and expression of leptin in LF tissues were determined. Then, the LF cells were cultured and exposed to recombinant human leptin (rhleptin). Collagen I and III were used as fibrosis markers and IL-6 was used as the inflammatory factor. As a result, the LF thickness and fibrosis score in the LSCS group were significantly higher than those in the LDH group (P<0.05). Leptin was detected in the hypertrophied LF and its expression was substantially increased in the LSCS group and positively correlated with LF thickness and fibrosis score (P<0.05). Moreover, our in vitro experiments revealed that rhleptin treated LF cells elevated the expression of collagen I and III. Finally, leptin administration induced IL-6 expression via nuclear factor-κB (NF-κB) pathway in LF cell (P<0.05). Our study demonstrated novel molecular events for leptin-induced inflammation in LF tissue by promoting IL-6 expression and thus might have potential implications for clarifying the mechanism underlying LF fibrosis and hypertrophy.

Insulin-Mediated Glucose Metabolism: An Atherogenic Lipid Profile of Fructose Consumption

Our laboratory has investigated two hypotheses regarding the effects of fructose consumption: 1) The endocrine effects of fructose consumption favor a positive energy balance, and 2) Fructose consumption promotes the development of an atherogenic lipid profile. In previous short- and long-term studies, we demonstrated that consumption of fructose-sweetened beverages with 3 meals results in lower 24-hour plasma concentrations of glucose, insulin, and leptin in humans compared with consumption of glucose-sweetened beverages. We have also tested whether prolonged consumption of high-fructose diets could lead to increased caloric intake or decreased energy expenditure, thereby contributing to weight gain and obesity. Results from a study conducted in rhesus monkeys produced equivocal results. Carefully controlled and adequately powered long-term studies are needed to address these hypotheses. In both short- and long-term studies we demonstrated that consumption of fructose-sweetened beverages substantially increases postprandial triacylglycerol concentrations compared with glucose-sweetened beverages. In the long-term studies, apolipoproteinB concentrations were also increased in subjects consuming fructose, but not those consuming glucose. Data from a short-term study comparing consumption of beverages sweetened with fructose, glucose, high fructose corn syrup (HFCS) and sucrose, suggest that HFCS and sucrose increase postprandial triacylglycerol to an extent comparable to that induced by 100% fructose alone. Increased consumption of fructose-sweetened beverages along with increased prevalence of obesity, metabolic syndrome, and type 2 diabetes underscore the importance of investigating the metabolic consequences fructose consumption in carefully controlled experiments.

Dexamethasone Down-regulates Osteocalcin in Bone Cells through Leptin Pathway

Glucocorticoid therapy, especially at higher doses, is associated with significant adverse side effects including osteoporosis. Leptin, secreted from adipose tissue, has diverse effects on bone tissue regulation. As glucocorticoids stimulate leptin synthesis and secretion directly in adipose tissue we hypothesised that dexamethasone (DEX) induced osteoporosis may, in part, be mediated by an osteoblast dependent leptin-leptin receptor pathway. Human bone cells expressed leptin and leptin receptors (Ob-Ra and Ob-Rb). DEX increased leptin, Ob-Ra and Ob-Rb expression in a dose-dependent manner while decreasing expression of osteocalcin. In the presence of leptin, Cbfa1 and osteonectin expression showed no significant change, whereas osteocalcin expression was decreased. Recombinant human quadruple antagonist leptin suppressed DEX-induced osteocalcin downregulation. The signaling pathway involved up-regulation of JAK2. In conclusion, upregulation of leptin and Ob-Rb in human bone cells by DEX is associated with down-regulation of osteocalcin expression. The down regulation of osteocalcin by DEX was partially through a leptin autocrine/paracrine loop. Adverse effects of DEX on the skeleton may be modified by targeting leptin signaling pathways.

Predictive Value of Serum Leptin in Systemic Sclerosis: A Novel Analytic Cross Sectional Study

Background: Systemic sclerosis (SSc) is a chronic autoimmune and multi-systematic connective tissue disease. Leptin is a cytokine like and has role in regulating immune and inflammatory response. Objectives: To assess predictive value of serum leptin in SSc patients. Methods: Analytic cross sectional study was performed on 40 SSc patients diagnosed according to the 1980 criteria for classification of systemic sclerosis or 2013 American College of Rheumatology/ European League against Rheumatism for the classification of systemic sclerosis criteria and compared with 40 healthy controls matched in age, sex, and body mass index. Serum leptin levels were measured using Human Leptin ELISA kit with a sandwich format. Results: Mean serum Leptin level was significantly higher in patients compared with controls ( Mean ± SEM was 10.89 ± 0.67 ng/ml Versus 6.92 ± 0.60 ng/ml, p 8.6 ng/ ml the test has highest accuracy of 80% with maximum sensitivity 82.5%, and specificity 77.5% and Mathew’s correlation coefficient (MCC) was 0.6. Also we can establish the diagnosis of SSc with 97.06 % confidence if the pretest probability of SSc was 90% and a negative result of the test can exclude the differential diagnosis of SSc with 97.6% confidence at 10% pretest probability. Conclusion: Serum leptin was a valid good measure to differentiate patients with SSc from healthy controls with high accuracy, sensitivity and specificity and PPV and NPV and good MCC.

The Relationship between Obstructive Sleep Apnea and Gln223Arg Polymorphism in Human Leptin Receptor Gene

Leptin is derived from an adipocyte and acts through the leptin receptor (LEPR). Gln223Arg polymorphism of the LEPR gene is thought to be associated with impaired signaling capacity of LEPR and with higher mean circulating levels of leptin and obesity; therefore, it may contribute to the pathogenesis of obstructive sleep apnea syndrome (OSAS). The aim of this study was to investigate the frequency of distribution of LEPR gene polymorphism (Gln223Arg) in OSAS patients in relation to polysomnographic traits and phenotype. In total, 230 men (152 OSAS patients and 78 controls) were included in the study. All participants were evaluated by polysomnography in addition to anthropometric, metabolic, and hemodynamic variables. The relationship between these phenotypes and polymorphism of the LEPR gene was investigated by PCR-RFLP. There was no difference between the genotype frequencies of the Gln223Arg polymorphism in the OSAS and control groups. However, OSAS patients carrying the R allele (RR and QR genotypes) had significantly lower Body Mass Index (BMI) than those carrying the Q allele (QQ). OSAS patients with the RR genotype had a significantly lower diastolic blood pressure value than those with the QQ and QR genotypes. When all participants were grouped by blood pressure, the genotype frequency of RR individuals was more prevalent among normotensive men compared to hypertensive men. Gln223Arg polymorphism of LEPR does not seem to be associated with OSAS. This polymorphism may, however, predispose the carrier to reduced BMI and blood pressure. Further studies are needed to unveil the genetic basis of OSAS pathophysiology.

Lysyl oxidase and adipose tissue dysfunction

Background/objectivesLysyl oxidase (LOX) is an enzyme crucial for collagen fibre crosslinking and thus for fibrosis development. Fibrosis is characterised by a surplus of collagen fibre accumulation and is amongst others also a feature of obesity-associated dysfunctional adipose tissue (AT) which has been linked with type 2 diabetes. We hypothesised that in type 2 diabetes and obesity LOX expression and activity will be increased as a consequence of worsening AT dysfunction. This study aimed to provide a comprehensive characterisation of LOX in human AT. MethodsLOX mRNA expression was analysed in omental and abdominal subcutaneous AT obtained during elective surgery from subjects with a wide range of BMI, with and without diabetes. In addition, LOX expression was studied in subcutaneous AT before and 9.5months after bariatric surgery. To study the mechanism of LOX changes, its expression and activity were assessed after either hypoxia, recombinant human leptin or glucose treatment of AT explants. In addition, LOX response to acute inflammation was tested after stimulation by a single injection of lipopolysaccharide versus saline solution (control) in healthy men, in vivo. Quantity of mRNA was measured by RT-qPCR. ResultsLOX expression was higher in obesity and correlated with BMI whilst, in vitro, leptin at high concentrations, as a potential feedback mechanism, suppressed its expression. Neither diabetes status, nor hyperglycaemia affected LOX. Hypoxia and lipopolysaccharide-induced acute inflammation increased LOX AT expression, latter was independent of macrophage infiltration. ConclusionsWhilst LOX may not be affected by obesity-associated complications such as diabetes, our results confirm that LOX is increased by hypoxia and inflammation as underlying mechanism for its upregulation in adipose tissue with obesity.

A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion

Adipocytes sense systemic nutrient status and systemically communicate this information by releasing adipokines. The mechanisms that couple nutritional state to adipokine release are unknown. Here, we investigated how Unpaired 2 (Upd2), a structural and functional ortholog of the primary human adipokine leptin, is released from Drosophila fat cells. We find that Golgi reassembly stacking protein (GRASP), an unconventional secretion pathway component, is required for Upd2 secretion. In nutrient-rich fat cells, GRASP clusters in close proximity to the apical side of lipid droplets (LDs). During nutrient deprivation, glucagon-mediated increase in calcium (Ca2+) levels, via calmodulin kinase II (CaMKII) phosphorylation, inhibits proximal GRASP localization to LDs. Using a heterologous cell system, we show that human leptin secretion is also regulated by Ca2+ and CaMKII. In summary, we describe a mechanism by which increased cytosolic Ca2+ negatively regulates adipokine secretion and have uncovered an evolutionarily conserved molecular link between intracellular Ca2+ levels and energy homeostasis.

Superactive human leptin antagonist (SHLA), triple Lan1 and quadruple Lan2 leptin mutein as a promising treatment for human folliculoma

PurposeThere are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.MethodsWe evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).ResultsObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.ConclusionThese results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.Graphical abstract

Effect of hormonal and energy-related factors on plasma adiponectin in transition dairy cows

In transition dairy cows, plasma levels of the insulin-sensitizing hormone adiponectin fall to a nadir at parturition and recover in early lactation. The transition period is also characterized by rapid changes in metabolic and hormonal factors implicated in other species as positive regulators of adiponectin production (i.e., negative energy balance, lipid mobilization) and others as negative regulators (i.e., reduced leptin and insulin and increased growth hormone and plasma fatty acids). To assess the role of onset of negative energy balance and lipid mobilization after parturition, dairy cows were either milked thrice daily (lactating) or never milked (nonlactating) for up to 4 wk after parturition. Plasma adiponectin was 21% higher across time in nonlactating than lactating cows. Moreover, nonlactating cows recovered plasma adiponectin at similar rates as lactating cows even though they failed to lose body condition. Next, we assessed the ability of individual hormones to alter plasma adiponectin in transition dairy cows. In the first experiment, dairy cows received a constant 96-h intravenous infusion of either saline or recombinant human leptin starting on d 8 of lactation. In the second experiment, dairy cows were studied in late pregnancy (LP, starting on prepartum d -31) and again in early lactation (EL, starting on d 7 postpartum) during a 66-h period of basal sampling followed by 48 h of hyperinsulinemic-euglycemia. In the third experiment, cows were studied either in LP (starting on d -40 prepartum) or EL (starting on d 7 postpartum) during a 3-h period of basal sampling followed by 5 d of bovine somatotropin treatment. Plasma adiponectin was reduced by an average of 21% in EL relative to LP in these experiments, but neither leptin, insulin, or growth hormone treatment affected adiponectin in LP or EL. Finally, the possibility that plasma fatty acids repress plasma adiponectin was evaluated by intravenous infusion of a lipid emulsion in nonpregnant, nonlactating cows in the absence or presence of glucagon for 16 consecutive hours. The intralipid infusion increased plasma fatty acid concentration from 102 to over 570 µM within 3 h but had no effect on plasma adiponectin irrespective of presence or absence of glucagon. Overall, these data suggest that energy balance around parturition may regulate plasma adiponectin but do not support roles for lipid mobilization or sustained changes in the plasma concentration of leptin, insulin, growth hormone, or fatty acids.

Chronic hyper-leptinemia induces insulin signaling disruption in adipocytes: Implications of NOS2

Leptin, following its discovery, has developed a formidable interest in the scientific community to delineate its contribution towards overall metabolic homeostasis. Contradictory reports have been published on leptin administration effects on whole body insulin sensitivity. Following late reports, we surveyed human serum leptin levels along with other metabolic parameters including BMI and HOMA-IR. We found a positive correlation between leptin levels and insulin resistance parameters. Considering the presence of the long form of leptin receptor on adipocytes, we explored the effects of chronic physiological hyper-leptinemic exposure on adipocyte insulin sensitivity. Chronic leptin (50ng/ml) treatment in 3T3-L1 adipocytes decreased insulin-induced phosphorylation of nodal insulin signaling proteins along with reduced glucose uptake. Metabolic flux studies indicated mitochondrial dysfunction and reduced oxygen consumption rate. Leptin treatment also increased both cellular and mitochondrial superoxide levels concomitant to increased expression of nitric oxide synthase-2 (NOS2). Further, pharmacological depletion of NOS2 reversed leptin mediated effects on insulin signaling. In-vivo implantation of leptin osmotic pumps in C57BL/6 mice also decreased insulin responsiveness. Interestingly, these effects were lacking in NOS2 knockout strain. In conclusion, our studies put forward a potential link between leptin and adipocyte insulin responsiveness in an NOS2 dependent manner.

Inter-relationship of serum leptin levels with selected anthropometric parameters among a non-diabetic population: a cross-sectional study.

Association between serum leptin levels and anthropometric parameter is well established in western countries according to the specific WHO cut-off values assigned for those populations, whereas it is not clearly defined for Asians especially with respect to gender. Thus, the objectives of this study were to determine the relationship of serum leptin levels with body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) to identify the variations of serum leptin levels with gender and to evaluate the serum leptin levels in risk and non-risk groups based on their anthropometric values. A cross-sectional study was carried out among 226 apparently healthy subjects (non-diabetics, age 20-70years). Height, weight, WC, hip circumference (HC) and mid arm circumference (MAC) were measured. BMI, WHR, waist to height ratio (WHtR) were calculated. Fasting blood samples were collected. Serum leptin levels were measured using human leptin ELISA kits. Majority of the participants were females (59.3%). Serum leptin levels were significantly higher in females (24.8±17.1ng/mL) compared to males (9.3±7.9ng/mL). Significant positive correlations (P<0.05) were observed between serum leptin levels and all anthropometric parameters except height in both genders. The risk groups according to BMI, WC and WHR in females were hyperleptinaemic and had significantly (P<0.05) higher serum leptin levels than the non-risk groups. Linear trend was observed for serum leptin levels with weight, BMI, WC, HC, WHR, MAC and WHtR in both genders. Though the serum leptin levels were higher among risk groups, according to WHR, WC and BMI, the hyperleptinaemia was observed only among females. A descriptive cross-sectional study, Level V.