Leptin Secretion Research Articles

Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

It has been previously shown that chronic ethanol administration-induced increase in adipose tissue lipolysis and reduction in the secretion of protective adipokines collectively contribute to alcohol-associated liver disease (ALD) pathogenesis. Further studies have revealed that increased adipose S-adenosylhomocysteine (SAH) levels generate methylation defects that promote lipolysis. Here, we hypothesized that increased intracellular SAH alone causes additional related pathological changes in adipose tissue as seen with alcohol administration. To test this, we used 3-deazaadenosine (DZA), which selectively elevates intracellular SAH levels by blocking its hydrolysis. Fully differentiated 3T3-L1 adipocytes were treated in vitro for 48 h with DZA and analysed for lipolysis, adipokine release and differentiation status. DZA treatment enhanced adipocyte lipolysis, as judged by lower levels of intracellular triglycerides, reduced lipid droplet sizes and higher levels of glycerol and free fatty acids released into the culture medium. These findings coincided with activation of both adipose triglyceride lipase and hormone sensitive lipase. DZA treatment also significantly reduced adipocyte differentiation factors, impaired adiponectin and leptin secretion but increased release of pro-inflammatory cytokines, IL-6, TNF and MCP-1. Together, our results demonstrate that elevation of intracellular SAH alone by DZA treatment of 3T3-L1 adipocytes induces lipolysis and dysregulates adipokine secretion. Selective elevation of intracellular SAH by DZA treatment mimics ethanol’s effects and induces adipose dysfunction. We conclude that alcohol-induced elevations in adipose SAH levels contribute to the pathogenesis and progression of ALD.

Effect of Obstructive Sleep Apnea on Bone Mineral Density.

Various studies have suggested that obstructive sleep apnea (OSA) affects bone metabolism. One of the most significant factors is hypoxia which induces certain transcription factors that stimulate bone osteoclastic activity. It also induces respiratory acidosis and oxidative stress which enhances bone resorption. Leptin and melatonin secretions are regulated by the circadian system which is affected due to sleep fragmentation in OSA. Other comorbidities associated with OSA such as vitamin D deficiency, hypogonadism, obesity, and insulin resistance are indirect mechanisms that affect bone mineral density (BMD). This is a prospective case-control study. All patients having symptoms of sleep-related breathing disorder (excluding post-menopausal females or patients with known case of osteoporosis or any other clinical illness which is a direct cause of osteoporosis) attending the Sleep Out Patient Department (OPD) were screened for OSA as per the STOPBANG questionnaire scoring system. Participants having score >2 constituted the final study population and were subjected to the polysomnography test. Participants with an apnea-hypopnea index (AHI) > 5 in polysomnography were considered as cases and those with AHI <5 were considered as controls. Both the groups were then subjected for dual-energy X-ray absorptiometry (DEXA) scan and vitamin D to establish a comparison. Out of 93 participants, 59 were taken as cases (OSA group), whose mean age was 48.02 (±8.435) years, mean body mass index (BMI) was 33.73 (±7.48) kg/m2, mean neck circumference was 37.8 cm (±5.08) as compared with the age, sex, and BMI matched non-OSA control group (n = 34). Mean BMD in the case group was found to be significantly on the lower side as compared with the control group (-2.02 ± 1.09 vs. -1.03 ± 0.97) (P < .001) when compared in Z score, while (0.885 ± 0.535 vs. 0.933 ± 0.616) when compared in g/cm2 (P < .001), with negative correlation between AHI and BMD (r = -0.507, P < .001). Mean vitamin D level in the case group was at a lower level as compared to the control group (21.02 ± 7.27 vs. 24.48 ± 6.92, P < .05), with negative correlation between AHI and serum vitamin D level (P < .001, r = -0.286). OSA affects BMD by various pathophysiologic mechanisms. The AHI is inversely correlated with BMD; that is, with increasing severity of OSA, there is a decrease in BMD.

α-Mangostin Alleviated Inflammation in Rats With Adjuvant-Induced Arthritis by Disrupting Adipocytes-Mediated Metabolism-Immune Feedback.

A previously identified anti-rheumatic compound α-mangostin (MAN) possesses notable metabolism regulatory properties. In this study, we investigated the immune implication of MAN-altered fat metabolism on adjuvant-induced arthritis (AIA) in rats. Seven days after AIA induction, the rats received oral treatment of MAN at 50 mg/kg/day for 30 days. Metabolic indicators and basic clinical parameters were evaluated using samples collected on day 20 and 38 since immunization. Expression of nicotinamide phosphoribosyltransferase (NAMPT), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma (PPAR-γ), stearoyl-coa desaturase 1 (SCD-1), toll like receptor 4 (TLR4), prostaglandin-endoperoxide synthase 2 (COX-2), (p)-JNK, (p)-p65 and IL-1β were investigated by either RT-qPCR or immunobloting methods. In in vitro experiments, we treated (pre)-adipocytes with monocytes/macrophages and MAN, and investigated the changes of macrophages brought by pre-adipocytes co-culture. Generally, MAN restored the impaired fat anabolism in AIA rats, indicated by increased fat reservoir, leptin and adiponectin secretion, and PPAR-γ and SCD-1 expression. Meanwhile, it decreased circulating IL-1β and IL-6 levels, restored serological lipid profile changes, and relieved oxidative stresses, demonstrating potent therapeutic effects on AIA. AIA rats-derived monocytes inhibited mRNA PPAR-γ and SCD-1 expression in pre-adipocytes. Contrarily, MAN facilitated adipocyte differentiation in vitro, and increased free fatty acids production. It also significantly increased PPAR-γ and SCD-1 expression, which can be abrogated by PPAR-γ inhibitor T0070907. Similarly, lipopolysaccharide-primed macrophages inhibited PPAR-γ expression in the co-cultured pre-adipocytes, which was reversed by MAN. In the same co-culture system, lipopolysaccharide-induced inflammation was amplified by the co-existence of pre-adipocytes. More secretion of IL-1β and IL-6 and higher levels expression of COX-2, p-JNK, p-p65 and TLR4 were observed in lipopolysaccharide-treated macrophages when co-cultured by pre-adipocytes. The intensified inflammatory situation was eased by MAN. The treatment with pre-adipocytes culture medium achieved similar effects. Medium from lipopolysaccharide-treated adipocytes promoted IL-1β, IL-6 and MCP-1 production in separately cultured macrophages, and COX-2, p-JNK, p-p65 and TLR4 expression were increased at the meantime. MAN treatment on pre-adipocytes impaired these changes. It suggests that fat anabolism in AIA rats was deficient due to increased energy expenditure caused by inflammatory conditions. MAN restored fat metabolism homeostasis by up-regulating PPAR-γ, and reshaped secretion profile of adipocytes.

Qing-Luo-Yin Alleviated Monocytes/Macrophages-Mediated Inflammation in Rats with Adjuvant-Induced Arthritis by Disrupting Their Interaction with (Pre)-Adipocytes Through PPAR-γ Signaling

BackgroundThe Chinese herbal formula Qing-Luo-Yin (QLY) has been successfully used in rheumatoid arthritis treatment for decades. It exhibits notable immune and metabolism regulatory properties. Thereby, we investigated its effects on the interplay between (pre)-adipocytes and monocytes/macrophages under adjuvant-induced arthritis (AIA) circumstances.MethodsFat reservoir and histological characteristics of white fat tissues (WAT) in AIA rats receiving QLY treatment were examined upon sacrifice. Metabolic parameters, clinical indicators, and oxidative stress levels were determined using corresponding kits, while mRNA/protein expression was investigated by PCR and immunoblotting methods. M1 macrophage distribution in WAT was assessed by flow cytometry. The effects of QLY on (pre)-adipocytes were further validated by experiments in vitro.ResultsCompared with normal healthy controls, body weight and circulating triglyceride were declined in AIA rats, but serological levels of free fatty acids and low-density lipoprotein cholesterol were increased. mRNA IL-1β and iNOS expression in white blood cells and rheumatoid factor, C-reactive protein, anti-cyclic citrullinated peptide antibody, MCP-1 and IL-1β production in serum/WAT were up-regulated. Obvious CD86+CD11b+ macrophages were enriched in WAT. Meanwhile, expression of PPAR-γ and SIRT1 and secretion of adiponectin and leptin in these AIA rats were impaired. QLY restored all these pathological changes. Of note, it significantly stimulated PPAR-γ expression in the treated AIA rats. Accordingly, QLY-containing serum promoted SCD-1, PPAR-γ, and SIRT1 expression in pre-adipocytes cultured in vitro. AIA rats-derived peripheral blood mononuclear cells suppressed PPAR-γ and SCD-1 expression in co-cultured pre-adipocytes, but serum from AIA rats receiving QLY treatment did not exhibit this potential. The changes on PPAR-γ expression eventually resulted in varied adipocyte differentiation statuses. PPAR-γ selective inhibitor T0070907 abrogated QLY-induced MCP-1 production decline in LPS-primed pre-adipocytes and reduced adiponectin secretion.ConclusionQLY was potent in promoting PPAR-γ expression and consequently disrupted inflammatory feedback in WAT by altering monocytes/macrophages polarization and adipocytes differentiation.

Findings from Studies Are Congruent with Obesity Having a Viral Origin, but What about Obesity-Related NAFLD?

Infection has recently started receiving greater attention as an unusual causative/inducing factor of obesity. Indeed, the biological plausibility of infectobesity includes direct roles of some viruses to reprogram host metabolism toward a more lipogenic and adipogenic status. Furthermore, the probability that humans may exchange microbiota components (virome/virobiota) points out that the altered response of IFN and other cytokines, which surfaces as a central mechanism for adipogenesis and obesity-associated immune suppression, is due to the fact that gut microbiota uphold intrinsic IFN signaling. Last but not least, the adaptation of both host immune and metabolic system under persistent viral infections play a central role in these phenomena. We hereby discuss the possible link between adenovirus and obesity-related nonalcoholic fatty liver disease (NAFLD). The mechanisms of adenovirus-36 (Ad-36) involvement in hepatic steatosis/NAFLD consist in reducing leptin gene expression and insulin sensitivity, augmenting glucose uptake, activating the lipogenic and pro-inflammatory pathways in adipose tissue, and increasing the level of macrophage chemoattractant protein-1, all of these ultimately leading to chronic inflammation and altered lipid metabolism. Moreover, by reducing leptin expression and secretion Ad-36 may have in turn an obesogenic effect through increased food intake or decreased energy expenditure via altered fat metabolism. Finally, Ad-36 is involved in upregulation of cAMP, phosphatidylinositol 3-kinase, and p38 signaling pathways, downregulation of Wnt10b expression, increased expression of CCAAT/enhancer binding protein-beta, and peroxisome proliferator-activated receptor gamma 2 with consequential lipid accumulation.

Expression of adipocytokine in heart fat depots depending on the degree of coronary artery atherosclerosis in patients with coronary artery disease

Background. In coronary artery disease, a change in the adipocytokine content of local fat depots of the heart is observed. However, it has not yet been established whether the expression levels of the studied parameters are really related to the degree of atherosclerotic lesion of the spacecraft.&#x0D; Aims to identify the features of the expression of adiponectin, leptin and IL-6 by adipocytes of epicardial, perivascular and subcutaneous adipose tissue depending on the degree of atherosclerotic lesion of the coronary channel in coronary heart disease.&#x0D; Materials and methods. The study conducted at the Research Institute for Complex Issues of Cardiovascular Disease in 20172020, included 84 patients with coronary heart disease (CAD), of which 39 with a moderate degree of atherosclerotic lesion of the coronary artery (CA) ( 22 points on the SYNTAX Score scale), 20 with severe (2331 points) and 25 with extremely severe ( 32 points). Biopsies of subcutaneous (SAT), epicardial (EAT) and perivascular adipose tissue (PVAT) were obtained during elective coronary artery bypass grafting (CABG). The expression of adipocytokine genes was determined using polymerase chain reaction (real-time PCR) using TaqMan probes and the concentration of the studied adipocytokines in adipocyte culture medium by enzyme immunoassay. Statistical analysis was performed using Statistica 9.0, a one-dimensional and multi-dimensional logistic regression analysis.&#x0D; Results. In CAD in adipocytes of the cardiac fat depot, a shift in the balance of adipocytokines is observed towards increased expression and secretion of leptin, IL-6 and a decrease in adiponectin with maximum manifestation in severe and extremely severe coronary lesions. Adipocytes of EAT were characterized by the minimal expression of the adiponectin gene against the background of the maximum leptin and IL-6 in comparison with adipocytes SAT and PVAT.&#x0D; Conclusions. Low expression of the adiponectin in EAT and PVAT against the background of increased expression of leptin and IL-6 is associated with an increase in the degree of atherosclerotic lesion of the coronary channel.

Oxytocin stimulates lipolysis, prostaglandin E2 synthesis, and leptin secretion in 3T3-L1 adipocytes

A model of oxytocin in the regulation of metabolic status has described one of oxytocin synthesis and release from the neurohypophysis in response to leptin, to suppress further leptin release. In addition, a lipogenic role for oxytocin has been suggested, consistent with an insulinergic action. This model, however, may be incorrect. Oxytocin reduces fat mass in the absence of either leptin or leptin receptor signalling, thereby challenging the interdependence between leptin and oxytocin. An oxytocin induced production of the anti-lipolytic prostaglandin E2 (PGE2) might account for this. Media from 3T3-L1 differentiated adipocytes treated with oxytocin (0–50 nmol.L−1) for 24 hrs were assayed for PGE2, leptin, adiponectin, and glycerol. Harvested cells were analysed for lipid droplet triglyceride and cytosolic free fatty acid (FFA) by flow cytometry, and for altered expression of lipolytic and lipogenic associated gene ontology transcripts by cDNA array. Both PGE2 and leptin secretion were significantly increased by oxytocin treatment whilst adiponectin secretion was not. A significant increase in cytosolic FFA was detected following oxytocin treatment, similar to that determined following treatment with isoproterenol (positive control). A significant increase in glycerol release to the culture media confirmed a lipolytic effect. No enrichment of lipolytic and lipogenic associated gene ontology transcripts was determined, but significant overrepresentation of chemosensory olfactory transcripts was. In conclusion, oxytocin stimulates lipolysis in 3T3-L1 adipocytes, mediated by autocrine/paracrine actions of PGE2 and leptin. To confirm that this response is mediated solely by the oxytocin receptor, further experiments would require those effects being blocked by a specific oxytocin antagonist.

High-throughput drug screening models of mature adipose tissues which replicate the physiology of patients’ Body Mass Index (BMI)

Obesity is a complex and incompletely understood disease, but current drug screening strategies mostly rely on immature in vitro adipose models which cannot recapitulate it properly. To address this issue, we developed a statistically validated high-throughput screening model by seeding human mature adipocytes from patients, encapsulated in physiological collagen microfibers. These drop tissues ensured the maintenance of adipocyte viability and functionality for controlling glucose and fatty acids uptake, as well as glycerol release. As such, patients’ BMI and insulin sensitivity displayed a strong inverse correlation: the healthy adipocytes were associated with the highest insulin-induced glucose uptake, while insulin resistance was confirmed in the underweight and severely obese adipocytes. Insulin sensitivity recovery was possible with two type 2 diabetes treatments, rosiglitazone and melatonin. Finally, the addition of blood vasculature to the model seemed to more accurately recapitulate the in vivo physiology, with particular respect to leptin secretion metabolism.

The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population

Background and aimsAt the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. Methods and resultsWe performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia–Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6–1.2) in Indonesian men, 1.1 (0.9–1.4) in Indonesian women, 2.2 (1.6–2.8) in Dutch men, and 1.2 (1.0–1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7–1.2), 0.8 (0.7–1.0), 0.6 (0.6–0.8), and 0.4 (0.4–0.5), respectively. ConclusionsDespite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.

CD40L/CD40 Regulates Adipokines and Cytokines by H3K4me3 Modification in Epicardial Adipocytes.

Epicardial adipose tissue (EAT) dysfunction mediates chronic inflammation by regulating inflammation-related adipokines and cytokines, and it further promotes coronary artery disease (CAD) development. CD40L/CD40 is involved in multiple inflammatory pathways that contribute to various pathophysiological processes. However, the function of CD40L/CD40 in the expression and production of adipokines and cytokines in epicardial adipocytes remains unclear. The purpose of the present study was to explore the role and underlying mechanisms of CD40L/CD40 in adipokine and cytokine expression and production. We isolated adipocytes from EAT tissues of CAD and non-CAD patients. We noticed that CD40 was dramatically increased in EAT tissues of CAD patients. Loss-of-function and gain-of-function studies were performed. The results showed that CD40 silencing reduced recombinant CD40 ligand (rCD40L)-induced upregulation of plasminogen activator inhibitor-1, leptin, interleukin-6, and monocyte chemotactic protein-1 messenger RNA levels and secretion. Overexpression of CD40 displayed the opposite results. In addition, rCD40L triggered mixed lineage leukemia protein-1 (MLL1) expression both in messenger RNA and protein levels. CD40 depletion apparently blocked MLL1 expression, whereas gain of function of CD40 resulted in augmentation of MLL1 levels. Interestingly, chromatin immunoprecipitation-quantitative real-time polymerase chain reaction analysis revealed that CD40 elimination dampened histone H3 lysine 4 trimethylation enrichment at plasminogen activator inhibitor-1, leptin, interleukin-6, and monocyte chemotactic protein-1 promoter regions in the presence of rCD40L. The reverse pattern was observed upon ectopic expression of CD40. Most important, MLL1 silencing effectively reversed the promotive effects of CD40 on adipokine and cytokine secretion. Taken together, our findings suggest that CD40L/CD40 regulates adipokine and cytokine expression by H3 lysine 4 trimethylation modification in adipocytes.

The Long-Term Effects of High-Fat and High-Protein Diets on the Metabolic and Endocrine Activity of Adipocytes in Rats.

Simple SummaryThe increasing prevalence of worldwide obesity and growing awareness of its negative consequences are forcing scientists to take a new view of nutrition and search for new diets. Therefore, to find some new relationships between diet and metabolism, we analyzed the effects of the long-term (60 and 120 days) use of a high-protein diet (HPD) and of a high-fat diet (HFD) on the metabolic and endocrine functions of fat tissue and on biochemical indices in rat blood in the present study. This research helped us to understand the roles of diet in the metabolic and endocrine functioning of adipocytes. Our study indicated that an HFD has a negative effect on fat tissue function, whereas the HPD showed positive results, such as increased insulin sensitivity and improved glucose and lipid metabolism in isolated adipocytes in vitro.The increasing prevalence of overweight and obesity and the rising awareness of their negative consequences are forcing researchers to take a new view of nutrition and its consequences for the metabolism of whole organisms as well as the metabolism of their individual systems and cells. Despite studies on nutrition having been carried out for a few decades, not many of them have focused on the impacts of these diets on changes in the metabolism and endocrine functions of isolated adipocytes. Therefore, we decided to investigate the effects of the long-term use (60 and 120 days) of a high-fat diet (HFD) and of a high-protein diet (HPD) on basic metabolic processes in fat cells—lipogenesis, lipolysis, and glucose uptake—and endocrine function, which was determined according to the secretion of adipokines into the incubation medium. Our results proved that the HPD diet improved insulin sensitivity, increased the intracellular uptake of glucose (p < 0.01) and its incorporation into lipids (p < 0.01) and modulated the endocrine function of these cells (decreasing leptin secretion; p < 0.01). The levels of biochemical parameters in the serum blood also changed in the HPD-fed rats. The effects of the HFD were inverse, as expected. We observed a decrease in adiponectin secretion and a diminished rate of lipogenesis (p < 0.01). Simultaneously, the secretion of leptin and resistin (p < 0.01) from isolated adipocytes increased. In conclusion, we noted that the long-term use of HPD and HFD diets modulates the metabolism and endocrine functions of isolated rat adipocytes. We summarize that an HFD had a negative effect on fat tissue functioning, whereas an HPD had positive results, such as increased insulin sensitivity and an improved metabolism of glucose and lipids in fat tissue. Moreover, we noticed that negative metabolic changes are reflected more rapidly in isolated cells than in the metabolism of the whole organism.

TELMISARTAN IMPROVES MYOCARDIAL REMODELING IN RATS WITH HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY THROUGH INHIBITING LEPTIN AUTOCRINE INDUCED BY ANGII AND ACTIVATING PPARGAMMA

Objective: The mechanism of left ventricular hypertrophy (LVH) in hypertension is complex. This study was to investigate the role of telmisartan in improving myocardial remodeling in hypertensive LVH and explore the potential molecular mechanism. Design and method: Eight-week male Sprague-Dawley (SD) rats were used to establish hypertensive LVH model through abdominal aortic constriction. Telmisartan was intragastrically administered 6weeks after surgery. Cardiac fibroblasts were used in vitro experiments under the treatment of angiotensin II (AngII), leptin or different inhibitors. The cardiac function and myocardial remodeling level were evaluated in rats, and the AngII-AT1R-ROS-ERK1/2-AP-1 pathway, leptin-JAK2/STAT3-TGF-β1/Smad3 pathway, and the metabolism-related parameters of collagen fibers were detected in cardiac fibroblasts. Results: Telmisartan treatment could alleviate left ventricular diastolic dysfunction (Table 1), reduce myocardial local RAAS and leptin level (Table 2), improve myocardial fibrosis and inhibit the activation of leptin-JAK2/STAT3-TGF-β1/Smad3 pathway in hypertensive LVH rats (Figure 1). AngII could increase the expression of leptin and induce AP-1 nuclear transposition in cardiac fibroblasts, and AT1R antagonist telmisartan, ROS scavenger NAC, ERK1/2 inhibitor PD98059 or AP-1 inhibitor SR11302 could inhibit leptin synthesis and secretion induced by AngII (Figure 2). Leptin could induce collagen metabolic disorders in cardiac fibroblasts, which could be partly restored by JAK2 inhibitor AG-490, STAT3 inhibitor S3I-201 or telmisartan. Telmisartan could reduce leptin synthesis and secretion as good as leptin antagonist, and improve collagen metabolism disorder induced by AngII better than leptin antagonist (Figure 3). Telmisartan could increase the expression of PPAR-γ to almost 3-fold of the control group. When pretreated with PPAR-γ inhibitor GW9662, telmisartan couldn’t restore the collagen metabolic disorders and the increased expression of P-STAT3 stimulated by leptin (Figure 4). Conclusions: Telmisartan can improve myocardial remodeling in hypertensive LVH rats via two ways: one is inhibiting leptin autocrine induced by local AngII as AT1R antagonist, the other is inhibiting leptin downstream signaling molecular STAT3 phosphorylation as PPAR-γ agonist (Figure 5). These findings demonstrate the crosstalk between myocardial local RAAS and leptin, and reveal a new molecular mechanism of telmisartan in improving myocardial remodeling in hypertensive LVH.

MICE EXPOSED TO EARLY LIFE STRESS SHOW SEX-SPECIFIC EFFECT OF WATOKINES ON ENDOTHELIAL FUNCTION

Abstract Objective: The aim of this study was to determine the effects of Maternal Separation and Early Weaning (MSEW), a mouse model of early life stress, on leptin production from different fat depots and the capacity of fat conditioned media to modulate the endothelial function of aortic ring in a sex-specific manner. Design and method: At weaning, control and MSEW mice were fed a high fat (HF, 16-weeks, 60% Kcal from fat). In one subset of mice, white adipose tissue (WAT) was collagenase-digested and preadipocytes counted by flow cytometry. In another subset of mice, ∼50 mg of freshly-isolated WAT was incubated in DMEM + 2% fatty acid free BSA (1 hour, 37°C) to measure leptin levels. Further, acetylcholine-induced relaxation in aortic rings from healthy mice (16-week-old fed a regular chow) was assessed to test how different fat depots media explants can modulate the endothelial function independently of the effects of MSEW on the vascular wall. Results: MSEW females showed a 20% increase in preadipocyte number in visceral-WAT vs. control (p &lt; 0.05). Fat-derived leptin secretion was similar between control and MSEW mice fed a low fat diet. However, HF increased leptin secretion in subcutaneous-WAT from male MSEW mice and visceral-WAT from female MSEW mice (p &lt; 0.05). Similarly, HF increased leptin mRNA in subcutaneous-WAT from male MSEW mice and visceral-WAT from female MSEW mice (p &lt; 0.05). Baseline vascular relaxation (48 ± 3 % relaxation at 5.5 x10–5mmol/L) was similarly impaired when aortic rings were incubated with perivascular adipose tissue (PVAT) media explants from female MSEW and control mice (25 ± 4 and 32 ± 2 % relaxation, respectively). However, rings incubated with visceral-WAT from female MSEW mice showed greater impairment of the vascular relaxation compared to controls (15 ± 3 and 29 ± 2 % relaxation, respectively, p &lt; 0.05). Male MSEW mice also displayed endothelial dysfunction in isolated rings; however, PVAT and visceral-VAT media explant induced a protective effect on endothelial function. Conclusions: Taken together this data indicates that there is a sex and depot-specific release of WATokines that could be an important factor modulating the vascular function in mice exposed to early life stress.

Expression of adipocytokines in heart fat depots depending on the degree of coronary artery atherosclerosis in patients with coronary artery disease.

In coronary artery disease (CAD) the adipocytokine content in the heart fat depot is altered, but it has not been established whether these changes are associated with the degree of atherosclerotic damage to the coronary artery (CA). Were examined 84 patients with CAD, and according to the degree of atherosclerotic state based on the SYNTAX Score scale, were divided: 39 moderate (≤22 points), 20 severe (23–31 points) and 25 extremely severe (≥32 points). Biopsies of subcutaneous (SAT), epicardial (EAT) and perivascular adipose tissue (PVAT) were obtained during elective coronary artery bypass grafting (CABG). The expression of adipocytokine was determined using real-time PCR. The concentration of the studied adipocytokines in adipocyte culture medium was measured by ELISA. Statistical analysis was performed using logistic regression analysis. In the adipocytes of the cardiac depot of patients with CAD, an increase in the expression and secretion of leptin and IL-6 and a decrease in adiponectin, with a maximum manifestation in severe and extremely severe CA lesions, was observed. EAT adipocytes were characterized by minimal expression of the adiponectin gene maximal gene expression leptin and IL-6 compared to SAT and PVAT adipocytes.

ROS Modulating Effects of Lingonberry (Vaccinium vitis-idaea L.) Polyphenols on Obese Adipocyte Hypertrophy and Vascular Endothelial Dysfunction.

Oxidative stress and dysregulated adipocytokine secretion accompanying hypertrophied adipose tissue induce chronic inflammation, which leads to vascular endothelial dysfunction. The present study investigated the ability of anthocyanin (ACN) and non-anthocyanin polyphenol (PP) fractions from lingonberry fruit to mitigate adipose tissue hypertrophy and endothelial dysfunction using 3T3-L1 adipocytes and human umbilical vein endothelial cells (HUVECs). This study showed that the PP fraction decreased intracellular ROS generation in hypertrophied adipocytes by enhancing antioxidant enzyme expression (SOD2) and inhibiting oxidant enzyme expression (NOX4, iNOS). Moreover, PP and ACN fractions reduced triglyceride content in adipocytes accompanied by downregulation of the expression of lipogenic genes such as aP2, FAS, and DAGT1. Treatment with both fractions modulated the mRNA expression and protein secretion of key adipokines in hypertrophied adipocytes. Expression and secretion of leptin and adiponectin were, respectively, down- and upregulated. Furthermore, PP and ACN fractions alleviated the inflammatory response in TNF-α-induced HUVECs by inhibiting the expression of pro-inflammatory genes (IL-6, IL-1β) and adhesion molecules (VCAM-1, ICAM-1, SELE). The obtained results suggest that consuming polyphenol-rich lingonberry fruit may help prevent and treat obesity and endothelial dysfunction due to their antioxidant and anti-inflammatory actions.

Phenotypic characterization of Adig null mice suggests roles for adipogenin in the regulation of fat mass accrual and leptin secretion

SummaryAdipogenin (Adig) is an adipocyte-enriched transmembrane protein. Its expression is induced during adipogenesis in rodent cells, and a recent genome-wide association study associated body mass index (BMI)-adjusted leptin levels with the ADIG locus. In order to begin to understand the biological function of Adig, we studied adipogenesis in Adig-deficient cultured adipocytes and phenotyped Adig null (Adig−/−) mice. Data from Adig-deficient cells suggest that Adig is required for adipogenesis. In vivo, Adig−/− mice are leaner than wild-type mice when fed a high-fat diet and when crossed with Ob/Ob hyperphagic mice. In addition to the impact on fat mass accrual, Adig deficiency also reduces fat-mass-adjusted plasma leptin levels and impairs leptin secretion from adipose explants, suggesting an additional impact on the regulation of leptin secretion.

Effect of High-Intensity Interval Training on Leptin, Adiponectin, and Leptin/Adiponectin Ratio in Overweight Adolescent Boys

Background: Proliferation of adipose tissue increases leptin secretion and decreases adiponectin concentration. Exercise is an intervention to control and reverse this process. Therefore, the present study aimed to determine the effect of 8-week high-intensity interval training on leptin, adiponectin, and the ratio of leptin to adiponectin in overweight adolescent boys. Materials and Methods: The present quasi-experimental study was conducted on overweight adolescent boys (13-18 years old, mean body mass index 27.05±1.4 kg/m2). A total of 30 participants volunteered who were divided into three groups of 10 people including short-term (9 sessions of 30-second training with 150-second rest), long-term (4 sessions of 150-second training with 240-second rest), and control group. The training groups performed high-intensity running sprints 3 times per week for 8 weeks. Data were analyzed using two-way repeated-measures ANOVA (3 groups×2 measurement times) and Bonferroni test. Results: Performed high-intensity interval training failed to affect leptin, weight, and body mass index but increased adiponectin and decreased the ratio of leptin to adiponectin (P = 0.042) and fat percentage. No difference was observed between the two types of interval training in changing the level of leptin, adiponectin, fat percentage, and body mass index. Conclusion: High-intensity interval training increases metabolic benefits in overweight adolescents by increasing adiponectin and subsequently decreasing the leptin/adiponectin ratio. Low exercise, no calorie restriction, and other factors affecting puberty may influence the research results.

Vitamin D Inhibits Adipokine Production and Inflammatory Signaling Through the Vitamin D Receptor in Human Adipocytes.

The purpose of this study was to investigate the effects of vitamin D on adipokine expression and inflammation in human adipose tissues and adipocytes and evaluate the molecular mechanisms involved. Omental and abdominal subcutaneous human adipose tissues were treated with 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), and adipokine levels were measured. Vitamin D effects were measured with or without dexamethasone because glucocorticoids are known to affect vitamin D actions. Using RNA interference, we examined whether the vitamin D receptor (VDR) mediated vitamin D actions on adipokine expression and inflammatory signaling pathways in human adipocytes. mRNA levels and secretion of leptin and IL-6 were suppressed by 1,25(OH)2 D3 in omental adipose tissues. Cotreatment with dexamethasone did not affect these inhibitory actions but partially blocked CYP24A1 induction. Similar results were observed in the subcutaneous depot. In addition, 1,25(OH)2 D3 suppressed leptin and IL-6 expression as well as nuclear factor-κB and extracellular signal-regulated kinase-1/2 phosphorylation in human adipocytes. Adipokine expression also was decreased by 25-hydroxyvitamin D3 (25(OH)D3 ), but not vitamin D3 . Knockdown of VDR increased the inflammatory signaling activity in the control condition and blocked the inhibitory effects of 1,25(OH)2 D3 on adipokine and inflammatory signaling pathways. Vitamin D acts through VDR to inhibit inflammatory pathways and adipokine expression in human adipocytes. Increasing vitamin D status may ameliorate obesity-associated metabolic complications by decreasing adipose tissue inflammation.

ADIPOQ and LEP variants on asthma and atopy: Genetic association modified by overweight.

Asthma and atopy are considered condition associated with obesity, being affected by genetic and environmental factors. The LEP and ADIPOQ genes, responsible for the expression and secretion of leptin and adiponectin, respectively, and polymorphisms in such genes have been linked to both diseases, independently, and also with the obesity-associated asthma phenotype in populations with high European ancestry and high-income countries. However, in mixed populations, there are few studies evaluating the impact of these variants in genes associated with the phenotype of asthma and obesity. Thus, the aim of this study was to investigate variants in LEP and ADIPOQ associated with asthma and atopy, and whether overweight modifies that effect. The study involved 203 asthmatics children and 813 control subjects (between 5 and 11years old), with or without overweight, from the SCAALA (Asthma and Allergy Social Changes in Latin America) program. Among them, 831 had data for allergy markers, being 258 atopic and 573 non-atopic. Genotyping was performed using a commercial panel Omnium Illumina 2.5. Logistic regression was performed to identify associations expected by using PLINK 1.09 and three genetic models: additive, dominant and recessive adjusted for sex, age, helminth infection, BMI and Principal Components (PC) 1 and 2, for ancestry, in order to control the confounding factor by population structure. For asthma, G allele of rs822396, in ADIPOQ, was positively associated in additive model (OR 1.4, 95% CI 1.08-1.83) and T allele of rs1063537 in dominant model (OR 1.52, 95% CI 1.01-2.30). In LEP, rs11763517 (C allele) and rs11760956 (A allele) were both negatively associated with asthma in the additive model (OR 0.70, 95% CI 0.54-0.91; OR 0.66, 95% CI 0.50-0.89) respectively, and the A allele of rs2167270 in dominant model (OR 0.71, 95% CI 0.51-0.98). The G allele of rs12706832 showed a positive association with asthma in the recessive model (OR 1.66, 95% CI 1.06-2.61). When the population was stratified by the BMI / Age Z-Score, the protection observed for asthma between the variants rs11760956, rs11763517 and rs2167270 was lost overweight individuals; The protection observed for atopy was lost in all variants (rs16861205, rs2167270 and rs17151919) in the overweight group. These results suggest that SNPs on the LEP and ADIPOQ genes may have an impact on atopy and asthma. Furthermore, we also show that the asthma and atopy protection attributed to variants on LEP and ADIPOQ genes is lost in individuals exposed to overweight.

LEPTIN: FROM APPETITE SUPPRESSION TO AUTOIMMUNITY

The hormone leptin is released by adipocytes accordingly to current energy stores to suppress appetite. Apart from this, leptin acts as a proinflammatory cytokine and strongly stimulates inflammation. Immune-modulating properties are partly achieved by affecting T-cell maturation, polarization, and viability. Leptin rises inflammatory cells count, increases proinflammatory cytokine secretion, and impairs regulatory T-lymphocytes differentiation. Leptin secretion and signalization disturbances have recently started to be observed in the context of autoimmunity. In this review, we discuss signaling pathways affected by the satiety hormone, its effect on T-lymphocyte maturation, differentiation and polarization, and relation to other immune-modulating agents. In the end, we highlight the rising evidence connecting hyperleptinemia state which is almost always related to obesity, with autoimmune disorders and take a brief overview of possible mechanisms behind leptin’s potency to induce self-reactivity.