Obesity Metabolic Disorders Research Articles

Association of Insulin Resistance and Ectopic Fat Accumulation with HOMA Indices: A Single-Centre Observational Study

Purpose: The aim of this study was to investigate the relationship between non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty pancreas (or pancreatic) disease (NAFPD) and HOMA indices in obese patients without a diagnosis of diabetes mellitus, using ultrasound (US) as a common non-invasive diagnostic tool during routine examinations. Methods: In this single-centre, retrospective study, the records of patients who applied to the obesity outpatient clinic in 2023 were reviewed. Digital records were scanned and patients with abdominal ultrasound reports indicating age, gender, body mass index(BMI), fasting plasma glucose, fasting plasma glucose, C-peptide level and degree of pancreatic and hepatic steatosis were included in the study. Patients with known chronic disease or diabetes mellitus and patients with specific drug use were excluded from the study. Homa indices were calculated using fasting plasma glucose and C-peptide levels. Results: A total of 62 patients were included. Body mass index was 39.1, 91% had NAFLD and 82% had NAFPD. There was a significant positive correlation between BMI and NAFLD and NAFPD. HOMA scores revealed a statistically significant impact of NAFLD on insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-S) but not on beta-cell function (HOMA-B). No significant effect of NAFPD on HOMA scores was observed. Conclusion: The findings underline the association between NAFLD and insulin resistance and highlight the metabolic burden of ectopic fat deposition in obese patients. In contrast, there was no significant correlation between NAFPD and either insulin resistance or beta-cell function, suggesting that the metabolic impact of pancreatic steatosis may be different. These findings may help to guide clinical strategies for detecting and treating metabolic disorders in obesity.

A new aspect of metabolic disorders in obesity: carbonyl stress

The literature review examines the problem of obesity in modern society. It has been shown that obesity aggravates concomitant diseases, increases the probability of developing metabolic disorders and related pathologies, increases the risk of complications and mortality. The secretory function of adipose tissue, its participation in the regulation of biological processes is considered in detail. The concept of carbonyl stress and its components is revealed, the role of carbonyl compounds in the body is described, the metabolic pathways leading to the formation of carbonyl reaction products are shown, the participation of free radicals in these metabolic pathways is noted. The mechanisms of pathogenesis associated with the development of carbonyl stress in obesity are discussed; the greatest contribution to the development of car bonyl pathology in obesity is made by two types of processes: lipid peroxidation reactions resulting in the formation of carbonyl products of lipoperoxidation and the processes activated by hyperglycemia (glycolysis, polyol and hexоzamine pathways) leading to the formation of glyoxal, methylglyoxal, and active carbonyl forms of glucose. The question of the contribution of advanced glycation end products (AGEs) and advanced oxidation protein products (AOРР) to the development of carbonyl pathology in obesity remains controversial. It is assumed that AGEs and AOРР levels depend on the severity of obesity and the development of metabolic syndrome.

LRP1 is the cell-surface endocytosis receptor for vaspin in adipocytes.

Vaspin is a serine protease inhibitor that protects against adipose tissue inflammation and insulin resistance, two key drivers of adipocyte dysfunction and metabolic disorders in obesity. Inhibition of target proteases such as KLK7 has been shown to reduce adipose tissue inflammation in obesity, while vaspin binding to cell surface GRP78 has been linked to reduced obesity-induced ER stress and insulin resistance in the liver. However, the molecular mechanisms by which vaspin directly affects cellular processes in adipocytes remain unknown. Using fluorescently labeled vaspin, we found that vaspin is rapidly internalized by mouse and human adipocytes, but less efficiently by endothelial, kidney, liver, and neuronal cells. Internalization occurs by active, clathrin-mediated endocytosis, which is dependent on vaspin binding to the LRP1 receptor, rather than GRP78 as previously thought. This was demonstrated by competition experiments and RNAi-mediated knock-down in adipocytes and by rescuing vaspin internalization in LRP1-deficient Pea13 cells after transfection with a functional LRP1 minireceptor. Vaspin internalization is further increased in mature adipocytes after insulin-stimulated translocation of LRP1. Although vaspin has nanomolar affinity for LRP1 clusters II-IV, binding to cell surface heparan sulfates is required for efficient LRP1-mediated internalization. Native, but not cleaved vaspin, and also vaspin polymers are efficiently endocytosed, and ultimately targeted for lysosomal degradation. Our study provides mechanistic insight into the uptake and degradation of vaspin in adipocytes, thereby broadening our understanding of its functional repertoire. We hypothesize the vaspin-LRP1 axis to be an important mediator of vaspin effects not only in adipose tissue but also in other LRP1-expressing cells.

NGR4 and ERBB4 as Promising Diagnostic and Therapeutic Targets for Metabolic Disorders.

Obese individuals are at high risk for developing type 2 diabetes mellitus, cardiovascular diseases, and nonalcoholic fatty liver disease. The aim of this review was to analyze the scientific literature and databases to reveal the fundamental role of neuregulin 4 (NRG4) and its receptors in the development of obesity-associated metabolic disorders. This review demonstrates that NRG4 and its receptors are promising therapeutic targets for the treatment of socially significant obesity-associated pathologies. The review contains nine chapters. Information on the structure of ERBB4 and NRG4 splice isoforms and subsequent activation of downstream targets is presented. The tissue-specific features of the NRG4 and ERBB4 genes and protein production are also highlighted. The role of NRG4 and ERBB3/4 in the pathophysiological mechanisms of the development of metabolic disorders in obesity is discussed in detail. The final chapter of the review is devoted to the miRNA-dependent regulation of NRG4 and ERBB4. Recent studies have shown that several miRNAs regulate ERBB4 expression, but no information was found on the interaction of NRG4 with miRNAs. We now demonstrate the putative relationships between NRG4 and let-7a-5p, let-7c-5p, miR-423-5p, miR-93-5p, miR-23a-3p, and miR-15b-5p for the first time. In addition, we found SNP mutations affecting the interaction of NRG4 and ERBB4 with miRNA in these genes as well as in miRNAs. In summary, this review provides a detailed and comprehensive overview of the role of NRG4 in obesity-associated metabolic disorders. The review summarizes all current studies on this topic and opens perspectives for future research.

Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Depot-Dependent Impact of Time-Restricted Feeding on Adipose Tissue Metabolism in High Fat Diet-Induced Obese Male Mice

Time-restricted feeding (TRF) is known to be an effective strategy for weight loss and metabolic health. TRF's effect on metabolism is complex and likely acts on various pathways within multiple tissues. Adipose tissue plays a key role in systemic homeostasis of glucose and lipid metabolism. Adipose tissue dysregulation has been causally associated with metabolic disorders in obesity. However, it is largely unknown how TRF impacts metabolic pathways such as lipolysis, lipogenesis, and thermogenesis within different in adipose tissue depots in obesity. To determine this, we conducted a 10-week TRF regimen in male mice, previously on a long-term high fat diet (HFD) and subjected the mice to TRF of a HFD for 10 h per day or ad libitum. The TRF regimen showed reduction in weight gain. TRF restored HFD-induced impairment of adipogenesis and increased lipid storage in white adipose tissues. TRF also showed a depot-dependent effect in lipid metabolism and restored ATP-consuming futile cycle of lipogenesis and lipolysis that is impaired by HFD within epididymal adipose tissue, but not inguinal fat depot. We demonstrate that TRF may be a beneficial option as a dietary and lifestyle intervention in lowering bodyweight and improving adipose tissue metabolism.

Obesity and diabetes - are they always together?

Obesity and type 2 diabetes mellitus (DM 2) are two interrelated metabolic diseases widespread throughout the developed world. However, up to 30% of individuals with a long history of obesity do not have a carbohydrate metabolism disorder. This article presents the results of a multi-year study of adipose tissue biology in obese individuals with DM 2 compared with individuals with the same history of obesity without DM 2. Comparative analysis of hormonal, cellular, and genetic factors in two groups of patients showed that DM 2 occurs in individuals with abnormal proliferation and adipogenic differentiation of mesenchymal stem cells (MSCs) of adipose tissue. It leads to adipocyte hypertrophy and inflammatory infiltration of adipose tissue macrophages, resulting in increased insulin resistance and diabetogenic effects. These disorders are due to abnormal expression of genes responsible for the proliferation and adipogenic differentiation of MSCs. The study of the possible reversibility of abnormal changes in adipose tissue MSCs in obese patients after significant weight loss and DM 2 remission appears to be a promising research direction. The ability to control adipose tissue progenitor cells may represent a new target for treating and preventing metabolic disorders in obesity.

Diabetic cardiomyopathy: a brief summary on lipid toxicity.

Diabetes mellitus (DM) is a serious epidemic around the globe, and cardiovascular diseases account for the majority of deaths in patients with DM. Diabetic cardiomyopathy (DCM) is defined as a cardiac dysfunction derived from DM without the presence of coronary artery diseases and hypertension. Patients with either type 1 or type 2 DM are at high risk of developing DCM and even heart failure. Metabolic disorders of obesity and insulin resistance in type 2 diabetic environments result in dyslipidaemia and subsequent lipid-induced toxicity (lipotoxicity) in organs including the heart. Although various mechanisms have been proposed underlying DCM, it remains incompletely understood how lipotoxicity alters cardiac function and how DM induces clinical heart syndrome. With recent progress, we here summarize the latest discoveries on lipid-induced cardiac toxicity in diabetic hearts and discuss the underlying therapies and controversies in clinical DCM.

T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity

Obesity is accompanied by inflammation in adipose tissue, impaired glucose tolerance, and changes in adipose leukocyte populations. These studies of adipose tissue from humans and mice revealed that increased frequencies of T-bet+ B cells in adipose tissue depend on invariant NKT cells and correlate with weight gain during obesity. Transfer of B cells enriched for T-bet+ cells exacerbates metabolic disorder in obesity, while ablation of Tbx21 specifically in B cells reduces serum IgG2c levels, inflammatory cytokines, and inflammatory macrophages in adipose tissue, ameliorating metabolic symptoms. Furthermore, transfer of serum or purified IgG from HFD mice restores metabolic disease in T-bet+ B cell-deficient mice, confirming T-bet+ B cell-derived IgG as a key mediator of inflammation during obesity. Together, these findings reveal an important pathological role for T-bet+ B cells that should inform future immunotherapy design in type 2 diabetes and other inflammatory conditions.

Serum Concentrations of Cartilage Intermediate Layer Protein 2 Were Higher in Overweight and Obese Subjects.

Background Cartilage intermediate layer protein 2 (CILP2) is associated with a variety of plasma lipoproteins and lipid traits. However, the correlation between CILP2 and obesity remains unknown. The aim of this study was to investigate the relationship between circulating CILP2 levels and obesity based on body mass index (BMI). Methods A total of 252 subjects were divided into three groups: normal weight (n = 124), overweight (n = 94), and obese (n = 34). Metabolic parameters were measured in a fasting state. Serum CILP2 concentration was tested by enzyme-linked immunosorbent assay. Multivariate linear regression analysis was used to explore the relationship between CILP2 and obesity. We also conducted bioinformatics analysis to further explore the genes and signaling pathways related to CILP2. Results The concentrations of serum CILP2 in the overweight and obese groups were significantly higher than that in the normal weight group. In multiple linear regression analysis, BMI was positively correlated with CILP2 concentration after controlling gender and age. Being overweight and obese were independently correlated with CILP2 concentration after adjusting for gender, age, SBP, DBP, FBG, 2-hour OGTT blood glucose (2h-BG), fasting blood insulin (FIns), TG, TC, HDL-C, LDL-C, and FFA. Bioinformatics analysis showed that the genes related to CILP2 are primarily associated with lipid metabolism and insulin resistance. Conclusion We speculate that CILP2 may attribute to metabolic disorders in obesity.

Accumulation of microbial DNAs promotes to islet inflammation and \u03b2 cell abnormalities in obesity in mice

Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and β cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in β cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into β cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into β cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in β cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in β cells and subsequently obesity-associated islet abnormalities.

In situ transplantation of adipose-derived stem cells via photoactivation improves glucose metabolism in obese mice

BackgroundAccumulating evidence suggests that enhanced adipose tissue macrophages (ATMs) are associated with metabolic disorders in obesity and type 2 diabetes. However, therapeutic persistence and reduced homing stem cell function following cell delivery remains a critical hurdle for the clinical translation of stem cells in current approaches.MethodsWe demonstrate that the effect of a combined application of photoactivation and adipose-derived stem cells (ASCs) using transplantation into visceral epididymal adipose tissue (EAT) in obesity. Cultured ASCs were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet (ND).ResultsIn diet-induced obesity, implantation of light-treated ASCs improved glucose tolerance and ameliorated systemic insulin resistance. Intriguingly, compared with non-light-treated ASCs, light-treated ASCs reduced monocyte infiltration and the levels of ATMs in EAT. Moreover, implantation of light-treated ASCs exerts more anti-inflammatory effects by suppressing M1 polarization and enhancing macrophage M2 polarization in EAT. Mass spectrometry revealed that light-treated human obese ASCs conditioned medium retained a more complete secretome with significant downregulation of pro-inflammatory cytokines and chemokines.ConclusionsThese data suggest that the combined application of photoactivation and ASCs using transplantation into dysfunctional adipose tissue contribute to selective suppression of inflammatory responses and protection from insulin resistance in obesity and type 2 diabetes.

Increased Prolactin is an Adaptive Response to Protect Against Metabolic Disorders in Obesity

ObjectiveProlactin (PRL) is a polypeptide hormone named for its crucial role in lactation. Recently, PRL has been recognized as a metabolic hormone that regulates energy metabolism. The current study aimed to investigate the relationship between circulating PRL and metabolic alterations in overweight/obese patients and the effect of weight loss through bariatric surgery on circulating PRL. MethodsA total of 448 overweight/obese patients aged between 18 and 40 years and 120 age- and sex-matched healthy controls with normal weight were enrolled. Among all participants, 156 obese patients underwent bariatric surgery. ResultsCirculating PRL levels were significantly increased in the overweight (15.27 ± 9.58 μg/L) and obese (17.75 ± 9.15 μg/L) groups compared with the normal weight (13.57 ± 9.03 μg/L) group. Multiple regression analyses demonstrated that the adipose tissue insulin resistance (adipo-IR) level was an independent predictor for PRL (β = −0.451, P < .01). Despite comparable anthropometric parameters, the overweight/obese patients with a higher PRL tertile had decreased levels of triglycerides, nonesterified fatty acids, homeostasis model assessment of insulin resistance, and adipo-IR compared with the patients in the moderate and lower PRL tertiles. Serum PRL levels were significantly decreased following the alleviation of metabolic parameters after bariatric surgery (from 17.12 ± 8.27 to 13.00 ± 5.78 μg/L, P < .05), and the decrease in PRL levels was significantly greater in the lower adipo-IR group than in the higher adipo-IR group (P < .01). ConclusionAn increased serum PRL level might be an adaptive response for protecting against metabolic disorders in obesity.

The crucial roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity

Abstract The prevalence of obesity is increasing worldwide. Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Analyzing deposited microarray data, we found transcripts for coagulation factors including factor VII (F7), factor X (F10), and PAR1 receptor were increased in BAT from obese mice. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. Fxa inhibition reduced reactive oxygen species (ROS) level in BAT. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. We generated BAT specific PAR1 KO mice. BAT-PAR1 KO mice exhibited re-browning of BAT along with reduced ROS level in this tissue. In BAT-PAR1 KO mice, glucose intolerance and thermogenic response under a metabolically stressed condition were ameliorated. In differentiated brown adipocytes, FXa markedly increased mitochondrial ROS and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes. Funding Acknowledgement Type of funding source: None

Obesity associated pro-fibrotic protein augments fibrosis in heart

Abstract Chronic sterile inflammation in visceral fat has causal roles for systemic metabolic disorders in obesity. Inflamed visceral adipose tissue secretes pro-inflammatory adipokines, and this contributes to tissue remodeling under a metabolically stressed condition. Various kinds of white adipokines are broadly studied, however, roles of brown adipose tissue (BAT) derived adipokines (BATokine) remain to be explored. In this project, we tried to characterize pathogenic role of BATokine in obesity related fibrotic disorders, especially focusing on heart failure with preserved ejection fraction (HFpEF). For this purpose, we analyzed two sets of DNA microarray data, and identified an obesity associated pro-fibrotic protein (OAFP) as a possible pathogenic BATokine. Our biobank studies showed OAFP increased in patients with diastolic dysfunction, and E/e' analyzed with cardiac echo increased in direct proportion to circulating OAFP level in humans. We generated dietary obese mice model, and found OAFP increased both in BAT and circulation. We generated a murine systemic or BAT specific OAFP knockout (KO) models, and found that obesity-induced diastolic dysfunction ameliorated in these models. Cardiac fibrosis was also suppressed by genetic depletion of OAFP. We found OAFP increased in circulation in aged humans and mice, and studies in chronologically aged mice showed this molecule increased in BAT with aging. Our results indicate that OAFP is secreted predominantly from BAT, and mediates pathogenic roles by augmenting cardiac fibrosis in dietary obesity or aging. Suppression of OAFP may become a therapy for HFpEF. Funding Acknowledgement Type of funding source: None

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance.

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

Protective Effect of α-Linolenic Acid on Non-Alcoholic Hepatic Steatosis and Interleukin-6 and -10 in Wistar Rats.

Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) is related to improvement in the inflammatory response associated with decreases in metabolic disorders of obesity, such as low-grade inflammation and hepatic steatosis. Linseed (Linum usitatissimum) oil is a primary source of n-3 fatty acids (FAs) of plant origin, particularly α-linolenic acid, and provides an alternative for the ingestion of n-3 PUFA by persons allergic to, or wishing to avoid, animal sources. In our study, we evaluated the effect of the consumption of different lipidic sources on metabolic and inflammatory parameters in Wistar rats. We split 56 male rats into four groups that were fed for 60 days with the following diets: sesame oil, (SO, Sesamum indicum), linseed oil (LO), SO + LO (SLO), and a control group (CG) fed with animal fat. Our results reveal that the use of LO or SLO produced improvements in the hepatic tissue, such as lower values of aspartate aminotransferase, liver weight, and hepatic steatosis. LO and SLO reduced the weight of visceral fats, weight gain, and mediated the inflammation through a decrease in interleukin (IL)-6 and increase in IL-10. Though we did not detect any significant differences in the intestine histology and the purinergic system enzymes, the consumption of α-linolenic acid appears to contribute to the inflammatory and hepatic modulation of animals compared with a diet rich in saturated FAs and or unbalanced in n-6/n-3 PUFAs, inferring possible use in treatment of metabolic disorders associated with obesity and cardiovascular diseases.

Serum adipokine concentrations in patients with type 2 diabetes: the relationships with distribution, hypertrophy and vascularization of subcutaneous adipose tissue

Academy of Sciences, Novosibirsk, Russia 2Novosibirsk State Medical University, Novosibirsk, Russia&#x0D; BACKGROUND: Adipose tissue (AT) dysfunction plays an important role in metabolic disorders in obesity and type 2 diabetes. The role of distribution, hypertrophy and vascularization of AT in adipokine secretion disturbances remain to be clarified.&#x0D; AIMS: To determine the relationships between serum concentrations of adipokines and the mass and distribution of AT, diameter of adipocytes and vascularization of subcutaneous AT in patients with type 2 diabetes.&#x0D; MATERIALS AND METHODS: A total of 125 patients were examined, including 82 subjects with obesity. Thirty persons without diabetes and obesity, matched by sex and age, were acted as control. Concentrations of leptin, resistin, visfatin, adipsin and adiponectin in fasting serum were determined using multiplex analysis. Mass and distribution of AT was assessed by dual-energy X-ray absorptiometry. Samples of SAT were obtained from umbilical region using a knife biopsy in 25 patients and in 15 individuals who died in accidents. Blood and lymphatic vessels in SAT were revealed with immunohistochemistry, using antibody to CD-34 and podoplanin respectively. The volume and numerical density, ultrastructure of blood and lymphatic vessels, and mean diameter of subcutaneous adipocytes were evaluated.&#x0D; RESULTS: Patients with diabetes, as compared to control, had significantly higher levels of leptin, resistin, adipsin and visfatin (all p0.001). Adiponectin showed no differences. Concentrations of leptin, resistin, visfatin, adipsin and adiponectin correlated positively with gynoid fat mass. Additionally, leptin and adipsinshowed positive correlations with truncal and central abdominal fat mass. Concentration of leptin, but not other adipokines, was associated with hypertrophy of subcutaneous adipocytes. A decrease in volumetric density of microvessels(р=0.01) and increase in volume and numerical density of lymphatic vessels (both р=0.02) was observed in subcutaneous AT from diabetic subjects. The swelling of cytoplasm, mitochondria, cisterns of granular endoplasmic reticulum and reduced content of micropinocytotic vesicles was revealed in lymphatic capillaries. Resistin and visfatin showed inverse associations with density of microvessels.&#x0D; CONCLUSION: Endocrine dysfunction of AT in patients with type 2 diabetes, manifested by elevation of serum concentrations of leptin, resistin, visfatin and adipsin, is associated with mass and distribution of AT, hypertrophy of subcutaneous adipocytes and vascularization abnormalities of subcutaneous AT.

3308The critical roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity

Abstract Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. BAT specific PAR1 KO mice improved glucose intolerance and thermogenic response under a metabolically stressed condition. In differentiated brown adipocytes, FXa markedly increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes.

Abstract 852: The Pathological Role of Coagulation Factors in Promoting Brown Adipose Tissue Dysfunction and Systemic Metabolic Disorder in Obesity

Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. BAT specific PAR1 KO mice improved glucose intolerance and thermogenic response under a metabolically stressed condition. In differentiated brown adipocytes, FXa markedly increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes