Obese Leptin Research Articles

The short-chain fatty acid acetate modulates orexin/hypocretin neurons: A novel mechanism in gut-brain axis regulation of energy homeostasis and feeding

The short-chain fatty acids (SCFAs) acetate, propionate and butyrate, the major products of intestinal microbial fermentation of dietary fibres, are involved in fine-tuning brain functions via the gut-brain axis. However, the effects of SCFAs in the hypothalamic neuronal network regulating several autonomic-brain functions are still unknown. Using NMR spectroscopy, we detected a reduction in brain acetate concentrations in the hypothalamus of obese leptin knockout ob/ob mice compared to lean wild-type littermates. Therefore, we investigated the effect of acetate on orexin/hypocretin neurons (hereafter referred as OX or OX-A neurons), a subset of hypothalamic neurons regulating energy homeostasis, which we have characterized in previous studies to be over-activated by the lack of leptin and enhancement of endocannabinoid tone in the hypothalamus of ob/ob mice.We found that acetate reduces food-intake in concomitance with a reduction of orexin neuronal activity in ob/ob mice. This was demonstrated by evaluating food-intake behaviour and orexin-A/c-FOS immunoreactivity coupled with patch-clamp recordings in Hcrt-eGFP neurons, quantification of prepro-orexin mRNA, and immunolabeling of GPR-43, the main acetate receptor. Our data provide new insights into the mechanisms of the effects of chronic dietary supplementation with acetate, or complex carbohydrates, on energy intake and body weight, which may be partly mediated by inhibition of orexinergic neuron activity.

Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Linking adipose tissue eosinophils, IL-4, and leptin in human obesity and insulin resistance.

BACKGROUNDObesity is a multifactorial disease with adverse health implications including insulin resistance (IR). In patients with obesity, the presence of high circulating levels of leptin, deemed hyperleptinemia, is associated with IR. Recent data in mice with diet-induced obesity (DIO) show that a partial reduction in leptin levels improves IR. Additional animal studies demonstrate that IL-4 decreases leptin levels. In rodents, resident adipose tissue eosinophils (AT-EOS) are the main source of IL-4 and are instrumental in maintaining metabolic homeostasis. A marked reduction in AT-EOS content is observed in animal models of DIO. These observations have not been explored in humans.METHODSWe analyzed AT from individuals with obesity and age-matched lean counterparts for AT-EOS content, IL-4, circulating leptin levels, and measures of IR.RESULTSOur results show that individuals with obesity (n = 15) had a significant reduction in AT-EOS content (P < 0.01), decreased AT-IL-4 gene expression (P = 0.02), and decreased IL-4 plasma levels (P < 0.05) in addition to expected IR (P < 0.001) and hyperleptinemia (P < 0.01) compared with lean subjects (n = 15). AT-EOS content inversely correlated with BMI (P = 0.002) and IR (P = 0.005). Ex vivo AT explants and in vitro cell culture of primary human mature adipocytes exposed to either IL-4 or EOS conditioned media produced less leptin (P < 0.05).CONCLUSIONOur results suggest that IL-4 acts as a link between EOS, AT, and leptin production. Future studies exploring this interaction may identify an avenue for the treatment of obesity and its complications through amelioration of hyperleptinemia.TRIAL REGISTRATIONClinicaltrials.gov NCT02378077 & NCT04234295.

Effects of exposure to environmental factors on obesity-related growth parameters and leptin (LEP) methylation in children.

The prevalence of childhood obesity is rapidly increasing. Therefore, gaining more information on the role of environmental parameters is key. With overexpression of leptin (encoded by LEP) in obesity, LEP methylation might be altered by environmental exposures. This study aims to assess effects of ambient air pollution and nearby greenness on obesity-related growth and LEP methylation in early childhood. We monitored 120 mother-child pairs from conception until the age of five. Buccal swabs and anthropometric measurements of the children were taken at six months, one year, and five years old. Buccal DNA was extracted to determine LEP methylation levels. Estimates of air pollution and nearby greenness were calculated using high-resolution models. Effects of air pollution and nearby greenness on growth or LEP methylation were investigated using linear mixed effects models. Positive associations were shown for air pollution between conception and age one on impedance in six-month-olds and one-year-olds in the crude model. PM with aerodynamic diameter ≤10 (PM10) and ≤2.5 μm (PM2.5) positively associated with waist-hip-ratio and waist circumference at age five in the fully adjusted model. In early childhood, closest distance to forest negatively, and urban green and forest positively associated with weight-for-length, body mass index, and fat percentage in five-year-olds in the fully adjusted model. No significant associations for noise, and walkability on growth were seen. Negative associations were shown for smaller green clusters and positive associations for greater green clusters on LEP methylation in one-year-olds. For forest distance, walkability, noise, or all green on LEP methylation, no significant associations were found. Evidence is provided that ambient air pollution might have a significant effect on impedance and waist-hip-ratio, suggesting an increased risk of childhood obesity. Based on LEP methylation, greater green clusters might associate with a decreased risk of childhood obesity, while smaller green clusters showed the opposite.

Obesity as a risk factor for chronic kidney disease: a contemporary view on the problem. Review

The review article is devoted to an actual clinical problem of participation of obesity in development and progression of chronic kidney disease (CKD). Some pathogenic links due to which a negative renal effect of obesity is mediated including in particular, dyslipidemia (DLP), endothelial dysfunction (ED) of renal vessels, activation of renin‑angiotensin‑aldosterone system (RAAS), arterial hypertension (AH), a production of adipose tissue mediators with renal injuring properties such as leptin, tumor necrosis factor‑α, interleukines 1,6,8 are discussed. The data about the main factors of progression of renal damage associated with obesity included insulin resistance (IR), hyperinsulinemia, DLP, systemic and renal hemodynamic disorders caused by activation of RAAS (AH, intraglomerular hypertension) are given. The role of metabolic syndrome and its components in pathogenesis of CKD as well as a role of diabetes mellitus (DM) frequently combined with obesity in development of diabetic kidney disease (diabetic nephropathy) is generalized. Among adipokines a special attention in the present review is paid for pathogenic role of leptin and adiponektin in obesity with its conditions promoted renal damage. The participation of resistance to leptin in the pathogenesis of CKD through such links as IR, ED, oxidative stress and inflammation is discussed. The role of ED and glomerular hyperfiltration in pathogenesis of microalbuminuria is elucidated. The significance of injury of kidney tubular cell structures so called podocytes in pathogenesis of CKD in obesity is uncovered. The clinical significance of early revealing of renal pathology as well as body weight, glycemia level, arterial blood pressure control and following of healthy mode of life in reduction of risk development of CKD associated with obesity, DM and other metabolic disorders is generalized. It’s emphasized that evaluation of lipid and carbohydrate exchange parameters, serum leptin level, IR indices is considered to be perspective for diagnostics of renal damage in obesity.

The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice

BackgroundCardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.MethodsTwo studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or non-parametric tests were used to compare two and multiple groups as appropriate.ResultsDasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.ConclusionsOur findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.

Modulation of Lymphangiogenesis in Incisional Murine Diabetic Wound Healing Using Negative Pressure Wound Therapy.

Objective: Despite the significant function of lymphatics in wound healing, and frequent clinical use of Negative Pressure Wound Therapy (NPWT), the effect of mechanical force application on lymphangiogenesis remains to be elucidated. We utilize a murine incisional wound healing model to assess the mechanisms of lymphangiogenesis following NPWT. Approach: Dorsal incisional skin wounds were created on diabetic mice (genetically obese leptin receptor-deficient mice [db/db]; n = 30) and covered with an occlusive dressing (Control, n = 15) or NPWT (-125 mmHg, continuous, 24 h for 7 days; NPWT, n = 15). The wounds were macroscopically assessed for 28 days. Tissue was harvested on day 10 for analysis. Qualitative functional analysis of lymphatic drainage was performed on day 28 using Evans Blue staining (n = 2). Results: NPWT increased lymphatic vessel density (40 ± 20 vs. 12 ± 6 podoplanin [PDPN]+ and 25 ± 9 vs. 14 ± 8 lymphatic vessel endothelial receptor 1 [LYVE-1]+) and vessel diameter (28 ± 9 vs. 12 ± 2 μm). Western blotting verified the upregulation of LYVE-1 with NPWT. Leukocyte presence was higher with NPWT (22% ± 3.7% vs. 9.1% ± 4.1% lymphocyte common antigen [CD45]+) and the leukocytes were predominately B cells clustered within vessels (8.8% ± 2.5% vs. 18% ± 3.6% B-lymphocyte antigen CD20 [CD20]+). Macrophage presence was lower in the NPWT group. Lymphatic drainage was increased in the NPWT group, which exhibited greater Evans Blue positivity. Innovation: The lymphangiogenic effects take place independent of macrophage infiltration, appearing to correlate with B cell presence. Conclusion: NPWT promotes lymphangiogenesis in incisional wounds, significantly increasing the lymph vessel density and diameter. This study highlights the potential of NPWT to stimulate lymphatic drainage and wound healing of surgical incisions.

Role of Leptin as a Link between Asthma and Obesity: A Systematic Review and Meta-Analysis.

Asthma and obesity are considered as highly prevalent diseases with a great impact on public health. Obesity has been demonstrated to be an aggravating factor in the pathogenesis of asthma. Adipose tissue secretes proinflammatory cytokines and mediators, including leptin, which may promote the development and severity of asthma in obese patients. This study is a systematic review and a meta-analysis based on the relationship between leptin and asthma during obesity. MEDLINE, Cochrane, EMBASE and CINAHL databases were used. Data heterogeneity was analyzed using Cochran's Q and treatment effect with the DerSimonian and Laird method. Random effect analyses were carried out to test data sensitivity. Asymmetry was estimated using Begg's and Egger's tests. All studies showed significant differences in leptin levels. The effect of the measures (p &lt; 0.001), data sensitivity (p &lt; 0.05) and data asymmetry were statistically significant, as well as tBegg's test (p = 0.010) and Egge's test (p &lt; 0.001). Despite the existing limiting factors, the results of this study support the relevant role of leptin in the pathophysiology of asthma in obese subjects. Nevertheless, further studies are needed to obtain better insight in the relationship between leptin and asthma in obesity.

A review: Effects of estrogen and estrogen receptor modulators on leptin resistance: Mechanisms and pathway

Obesity is characterized by an increase in food intake and a decrease in energy expenditure, which causes the accumulation of fat in the body, resulting in various disorders such as type 2 diabetes and cancer. Adipocytes secrete the hormone leptin, and leptin signaling plays an essential role in regulating energy balance. Leptin reduces food intake and increases energy expenditure by binding to its receptors in the hypothalamus and regulating appetite-regulating neurons. Accumulation of excess fat along with increased blood levels of leptin impairs the passage of leptin across the blood-brain barrier and induces leptin resistance. Estrogen also plays an important role in regulating energy balance due to the expression of its receptors in the hypothalamus, and its deficiency is associated with increased food intake and body weight, and estrogen therapy is able to partially mimic the effects of leptin. In this review, we get familiar with the concept of leptin resistance and its mechanisms, and finally, we examine the role of estrogen by emphasizing the mechanisms of energy balance regulation. • Increased inflammation and high levels of leptin in obesity lead to leptin resistance. • Estrogen via ERα increases p-STAT3 signaling in the ARC of hypothalamus and reduces leptin resistance. • Estrogen via ERα reduces inflammation, NPY, and AgRP levels and increases α-MSH. • Tamoxifen as a SERM, reduces leptin resistance by reducing inflammation and modulating brain neuropeptides. • Aging is an influential factor contributing to leptin responsiveness in presence of estrogen, which reduces the effects of estrogen.

Hepatokine Fetuin B expression is regulated by leptin-STAT3 signalling and associated with leptin in obesity

Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.

The association between variant rs9939609 in the FTO gene with free leptin index and the risk of obesity in the Indonesian children population

BackgroundSeveral studies have reported that fat mass and obesity-associated gene (FTO), especially the rs9939609 polymorphism, are associated with obesity and high leptin levels. The free leptin index (FLI) is known to be accurate in determining the function of leptin. The aim of this study was to determine the association between the rs9939609 variant in the FTO gene and FLI and the risk of obesity among children living in Medan, Indonesia.MethodsThis case–control study included 212 children aged 6–12 years who were genotyped for variants of the rs9939609 FTO gene. The case group consisted of children with obesity who were < 6 years old, and the control group had a normal body mass index and came from the Bataknese or Chinese ethnicities. Anthropometric measurements were performed. Serum leptin and soluble leptin receptor (sOB-R) levels were measured. Odds ratio and 95% confidence intervals were calculated to determine the risk of having obesity associated with the risk allele.ResultsIn this study, there was no significant association between leptin, soluble leptin receptor, or free leptin index and the rs9939609 FTO gene; however, the risk allele (A) of FTO rs9939609 had a significant association with obesity in Chinese ethnicity subjects (p < 0.05). The AA/AT genotype had an increased risk of FLI 5.889 times compared to the TT genotype. Multivariate analysis showed that the rs9939609 polymorphism in the FTO gene played a role in obesity through the FLI.ConclusionIt was concluded that the rs9939609 polymorphism played a significant role in obesity through FLI. Further studies are still needed.

Human Amniotic Membrane Promotes Angiogenesis in an Oxidative Stress Chronic Diabetic Murine Wound Model.

Objective: The development of animal models, which adequately replicate the pathophysiology of chronic wounds, has been challenging. In this study, we utilized an oxidative stress (OS) murine model, which was previously developed by our group, to study the effect of a human amniotic membrane (AM) on chronic wound healing. Approach: Forty-five diabetic (genetically obese leptin receptor-deficient mice [db/db]) mice were separated into three groups. Thirty mice received an OS regimen and a 1 - × 1 cm2 full-thickness excisional dorsal wound. The wounds were either covered with AM and occlusive dressing (db/dbOS-AM) or occlusive dressing only (db/dbOS). Fifteen mice did not receive the OS regimen, and were covered with AM and occlusive dressing (db/db-AM). The wounds were photographed, and tissue was harvested at various time points. Results: Vascular density was higher in the AM-treated groups (db/dbOS-AM: 34 ± 12; db/db-AM: 37 ± 14; vs. db/dbOS: 19 ± 9 cluster of differentiation 31 [CD31+]/high power field [HPF] photograph; p = 0.04 and p = 0.003). Vessel maturity was lowest in the db/dbOS group (21% ± 4%; vs. db/dbOS-AM: 38% ± 10%, p = 0.004; db/db-AM: 40% ± 11%, p = 0.0005). Leukocyte infiltration was higher in the AM groups (db/dbOS-AM: 15 ± 4; db/db-AM: 16 ± 4 vs. db/dbOS: 8 ± 3 lymphocyte common antigen [CD45+]/HPF; p = 0.005 and p = 0.06). AM upregulated various proangiogenic factors, including vascular endothelial growth factor (VEGF), and downregulated genes involved in chronicity, such as osteopontin, as visualized through proteome analysis and western blotting. Cell death was lower in the AM groups (db/dbOS-AM: 28 ± 10, db/db-AM: 7 ± 5 vs. db/dbOS: 17% ± 9% Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL+]; p = 0.03 and p < 0.0001). Innovation: This study offers new insight on the mechanisms of action of human AM in chronic wound healing. Conclusion: AM treatment promoted healing in mice with complex chronic wounds. The AM stimulated angiogenesis through upregulation of proangiogenic factors, improving the wound milieu by increasing leukocyte and growth factor delivery and decreasing cell death.

Leptin in obesity and hypertension

Background: Obesity along with hypertension is the common risk factor for the development of cardiovascular disease. Leptin, an anti-obesity hormone, is currently considered to play a vital role in the development of hypertension in obesity. We aim to determine the leptin levels in hypertensive and normotensive participants and to find the correlation between leptin and hypertension in obese and non-obese hypertensive subjects. Material and methods: A total of 94 participants aged &gt; 18years of either gender were included in the study. The participants were divided into obese (n = 55) and non-obese (n = 39) groups with further subgroups based on presence or absence of hypertension. Height, weight and blood pressure were taken with standard methods. Leptin was determined using ELISA method and intra and inter-group comparisons were made. Results: The leptin levels were significantly higher in obese (p = 0.000), hypertensive (p = 0.048) and females (p = 0.001) compared to non-obese, normotensive and male participants. Furthermore, obese hypertensive participants were having higher leptin levels compared to obese normotensive participants but with no statistical significance (p = 0.14). Serum leptin levels positively correlated with serum LDL (p = 0.003), body mass index (BMI) (p = 0.000), serum uric acid (p = 0.034) and fasting plasma glucose (FPG) (p = 0.001). However, on correction for factors like BMI, and obesity, positive correlation persisted only for female gender (p = 0.048) and FPG (p = 0.029). Furthermore, BMI (p = 0.021) and FPG (p = 0.027) were found to be the independent risk factors for elevated leptin levels on multiple regression analysis. Conclusions: Our study concluded that serum leptin levels are higher in obesity and have a direct correlation with degree of obesity. However, our study does not support any direct correlation between serum leptin and hypertension.

The role of leptin and low testosterone in obesity.

Obesity is a medical condition associated with metabolic disorders and low-grade systemic inflammation. Another characterizing feature of obesity is high circulating levels of leptin (a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance), a phenomenon termed hyperleptinemia. Hyperleptinemia is associated with both low-grade systemic inflammation and metabolic dysfunction in obese human beings. Moreover, obesity is associated with low testosterone in men, which correlates with high body fat. The association between leptin and low testosterone could potentially be explained via the imbalanced leptin levels that results in higher estrogen levels, which further increases the aromatase activity. The increase in aromatase activity in turn reciprocally inhibits the testosterone levels and hypothalamic pituitary gonadal axis. Novel strategies are being used to treat obesity, including leptin and testosterone therapy. However, the efficacy and adverse effects of these strategies need further validation through preclinical and clinical studies. Additionally, further studies are needed to establish the molecular mechanism behind leptin-modulated changes to testosterone in obese men. This review summarizes the available literature on the role of leptin and low testosterone during obesity.

Static Magnetic Fields Reduce Oxidative Stress to Improve Wound Healing and Alleviate Diabetic Complications.

Although some studies have shown that some static magnetic fields (SMFs) can promote wound healing in diabetic mice, it is not clear whether the other diabetes complications, such as liver disease and diabetic nephropathy, can also be alleviated. Here, we constructed two simple magnetic plates using neodymium permanent magnets to examine the comprehensive effects of moderate SMFs on genetically obese leptin receptor-deficient db/db diabetic mice. We found that although the blood glucose was not obviously reduced by these two SMF settings, both of the glycated serum protein (GSP) and malondialdehyde (MDA) levels were significantly decreased (Cohen’s d = 2.57–3.04). Moreover, the wound healing, liver lipid accumulation, and renal defects were all significantly improved by SMF treatment (Cohen’s d = 0.91–2.05). Wound tissue examination showed obvious nuclear factor erythroid 2-related factor 2 (NRF2) level decrease (Cohen’s d = 2.49–5.40) and Ki-67 level increase (Cohen’s d = 2.30–3.40), indicating decreased oxidative stress and increased cell proliferation. In vitro cellular studies with fibroblast NIH3T3 cells showed that SMFs could reduce high glucose-induced NRF2 nucleus translocation (Cohen’s d = 0.87–1.15) and cellular reactive oxygen species (ROS) elevation (Cohen’s d = 0.92), indicating decreased oxidative stress. Consequently, high glucose-induced impairments in cell vitality, proliferation, and migration were all improved by SMF treatment. Therefore, our results demonstrate that these simple SMF devices could effectively reduce oxidative stress in diabetic mice and may provide a cost-effective physical therapy strategy to alleviate multiple diabetic complications in the future.

Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells invitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Leptin Concentrations in Non-Obese and Obese Non-Diabetes Nigerian-Africans

BackgroundControversial findings exist on the role of leptin in obesity and its correlation with metabolic variables, with few data emanating from Nigerian-Africans. Plasma leptin was therefore determined in obese and non-obese. Its relationship with obesity indices and metabolic variables were further envisaged.Materials and MethodsA cross-sectional comparative study on 87 randomly-selected non-diabetes Nigerians distributed into 3 groups (24 normal, 23 pre-obese and 40 obese). Obesity indices, fasting Insulin (FI) and homeostasis model assessment-insulin resistance (HOMA-IR) were determined. Plasma leptin was determined by sandwich enzyme-linked immunosorbent assay. Mann-Whitney U-test, Independent Kruskal-Wallis test, Spearman correlation and Step-wise Multivariate Logistic Regression analysis determined outcomes.ResultsMedian+IQR leptin concentrations were higher in obese {61.8(40.8, 91.4) ng/mL, p<0.001} than pre-obese {42.7(28.0, 51.7) ng/mL, p=0.003} and normal {28.6(20.7, 39.8) ng/mL, p=0.03} BMI categories. Leptin was higher (p<0.001) in females than males {Median+IQR, 52.0 (35.0, 80.0) ng/mL versus 34.0(24, 65.0 ng/mL)}. Leptin was positively correlated with body fat percentage (BFP), r=0.57; waist circumference (WC), r=0.46 and body mass index (BMI), r=0.50, p<0.001, respectively in all subjects, with higher correlation coefficient in males than females. Leptin showed sex-specific correlations to age, FI and HOMA-IR. In the unadjusted models, central obesity/generalized obesity, WC, BMI, BFP, combined pre-obesity/obesity, younger age and female sex were significantly (p<0.001) associated with log-transformed leptin. WC (OR: 1.2, 95% CI, 1.05–1.38, p=0.009), BFP (OR: 1.41, 95% CI, 1.07–1.84, p=0.013) and BMI (OR: 1.6, 95% CI, 1.13–2.31, p=0.008) in men and all subjects, were independently associated with hyperleptinaemia following adjustments.ConclusionPlasma leptin concentrations, fasting insulin and insulin resistance are higher in obese and pre-obese than normal controls, with females showing higher leptin concentrations than males. Leptin is independently related to BMI, BFP, WC, female sex and generalized/central obesity in Nigerian-Africans especially males. It showed sex-specific relations to age, fasting insulin and HOMA-IR.

Abdominal obesity and adipocyte metabolic activity: criteria for "health" and "neutrality"

The last decades of the late 20th and early 21st centuries have seen a rapid growth of non-infectious diseases such as abdominal obesity, prehypertension, hypertension, diabetes mellitus type 2. According to official data, preobesity is diagnosed in 40.1% of the adult population of Russia; 21.6% of Russians are obese; and only 36.3% of our fellow citizens have normal body weight. The combination of obesity, hypertension, diabetes mellitus type 2 and atherogenic dyslipidemia are the criteria for metabolic syndrome a proven risk factor for progression and complicated course of cardiovascular disease. The scientific community is actively discussing about the appropriateness of singling out a group of patients with metabolically healthy obesity and criteria for its diagnosis, but the hormonal activity of adipose tissue is not evaluated. Leptin is involved in the metabolism of glucose and fatty acids, and leptinresistance is an important prognostic marker of the complicated obesity. On the based of our own scientific data results, the concept of metabolically neutral obesity - obesity with normal adipokines activity (leptin concentration 3.5 ng/ml) without signs of insulinresistance was formulated and proposed. It was shown that in this metabolic type of obesity the prevalence of dyslipidemia was 1.7 times, prediabetes 2 times, atherosclerosis of common carotid arteries 1.5 times lower than in metabolically healthy obesity. Determining the level of leptin in uncomplicated obesity allows stratifying patients into groups with normal and increased adipokines activity. The highlighting of the metabolically neutral type of obesity is considered by us to be practically justified, as it allows to determine the stage of the disease at which the frequency of metabolic and cardiovascular disorders is still minimal and non-drug prevention is necessary. Exceeding the threshold of leptin level 3.5 ng/ml in obesity may require a more aggressive lifestyle correction, and possibly an early start to drug therapy.

Leptin and obesity.

An imbalance between calorie intake and energy expenditure produces obesity. It has been a major problem in societies of the developing and developed world. In obesity an excessive amount of fat accumulates in adipose tissue cells as well as in other vital organs like liver, muscles, and pancreas. The adipocytes contain ob genes and express leptin, a 16 kDa protein. In the present communication, we reviewed the molecular basis of the etiopathophysiology of leptin in obesity. Special emphasis has been given to the use of leptin as a drug target for obesity treatment, the role of diet in the modulation of leptin secretion, and reduction of obesity at diminished level of blood leptin induced by physical exercise.

Fluctuations in depression and anxiety predict dysregulated leptin among obese breast cancer survivors.

Leptin influences inflammation and tumor growth and leptin signaling is often dysregulated among obese breast cancer survivors. This leads to a lack of satiety and, ultimately, risk for further weight gain. Breast cancer survivors also experience high rates of depression and anxiety, which are linked to leptin production. This study examined how a woman's anxiety and depressive symptoms, in combination with their obesity status, were associated with leptin. Breast cancer survivors (n= 200, stages 0-IIIa) completed a baseline visit before treatment and two follow-up visits, 6 and 18months after treatment ended. Women completed anxiety and depression measures, and blood samples provided leptin data at each visit. This study related fluctuations in a survivor's own depression and anxiety (i.e., within-person effects), as well as average effects of depression and anxiety (i.e., between-person effects) to changes in leptin depending on BMI. Obese survivors' leptin was significantly higher at visits when they had higher anxiety and depression symptoms than their own average level of symptoms. In contrast, within-person fluctuations in depression and anxiety were not related to leptin levels among non-obese survivors. No significant between-person effects of depression or anxiety on leptin emerged. Leptin is a critical risk factor for recurrence and further health consequences. Our findings highlight how psychological health influences leptin production among breast cancer survivors. These results highlight a biological pathway that may facilitate further weight gain and health risks among distressed, obese breast cancer survivors.