Visceral Adipose Tissue Gene Expression Research Articles

The association of dietary insulinemic indices with PI3K, PTEN, and Akt gene expressions in visceral and subcutaneous adipose tissues among individuals undergoing abdominal surgery.

The current study investigates the association between dietary insulinemic indices and Akt, PTEN, and PI3K gene expressions in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) among individuals undergoing abdominal surgery. This cross-sectional study was conducted on 176 individuals, aged 18-84 years, who had undergone abdominal surgery. The participants were classified based on body mass index (BMI) as normal (BMI < 25 kg/m2), overweight (BMI = 25-29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The food frequency questionnaire was used to determine dietary glycemic and insulinemic indices. Real-time polymerase chain reaction was conducted for the expression of PI3K, PTEN, and Akt genes. In the final adjusted model, in normal-weight patients, there was an inverse relationship between the lifestyle with a higher insulinemic potential and the PI3K gene expression in VAT. In addition, there was an inverse association between dietary insulin load and the Akt gene expression in VAT. However, a higher glycemic index was positively associated with the PTEN gene expression in VAT. In overweight patients, a high insulinemic potential of the diet was associated with higher PTEN gene expression in VAT. In obese individuals, there were positive associations between lifestyle index for insulin resistance and hyperinsulinemia and the PI3K gene expression in VAT. Moreover, the higher insulinemic potential of diet and lifestyle was positively related to a higher expression of the PTEN and Akt genes in VAT. Our findings revealed that high insulinemic lifestyles and dietary patterns may be related to the expression of PI3K, PTEN, and Akt in adipose tissues.

Clinical and molecular profiling of human visceral adipose tissue reveals impairment of vascular architecture and remodeling as an early hallmark of dysfunction

Adipose tissue dysfunction is more related to insulin resistance than body mass index itself and an alteration in adipose tissue function is thought to underlie the shift from metabolically healthy to unhealthy obesity. Herein, we performed a clustering analysis that revealed distinct visceral adipose tissue gene expression patterns in patients with obesity at distinct stages of metabolic dysregulation. We have built a cross-sectional cohort that aims at reflecting the evolution of the metabolic sequelae of obesity with the main objective to map the sequential events that play a role in adipose tissue dysfunction from the metabolically healthy (insulin-sensitive) state to several incremental degrees of metabolic dysregulation, encompassing insulin resistance establishment, pre-diabetes, and type 2 diabetes. We found that insulin resistance is mainly marked by the downregulation of adipose tissue vasculature remodeling-associated gene expression, suggesting that processes like angiogenesis and adaptative expansion/retraction ability suffer early dysregulation. Prediabetes was characterized by compensatory growth factor-dependent signaling and increased response to hypoxia, while type 2 diabetes was associated with loss of cellular response to insulin and hypoxia and concomitant upregulation of inflammatory markers. Our findings suggest a putative sequence of dysregulation of biological processes that is not linear and has multiple distinct phases across the metabolic dysregulation process, ultimately culminating in the climax of adipose tissue dysfunction in type 2 diabetes. Several studies have addressed the transcriptomic changes in adipose tissue of patients with obesity. However, to the best of our knowledge, this is the first study unraveling the potential molecular mechanisms associated with the multi-step evolution of adipose tissue dysfunction along the metabolic sequelae of obesity.

Drastic transformation of visceral adipose tissue and peripheral CD4 T cells in obesity.

Obesity has a pronounced effect on the immune response in systemic organs that results in not only insulin resistance but also altered immune responses to infectious diseases and malignant tumors. Obesity-associated microenvironmental changes alter transcriptional expression and metabolism in T cells, leading to alterations in T-cell differentiation, proliferation, function, and survival. Adipokines, cytokines, and lipids derived from obese visceral adipose tissue (VAT) may also contribute to the systemic T-cell phenotype, resulting in obesity-specific pathogenesis. VAT T cells, which have multiple roles in regulating homeostasis and energy utilization and defending against pathogens, are most susceptible to obesity. In particular, many studies have shown that CD4 T cells are deeply involved in the homeostasis of VAT endocrine and metabolic functions and in obesity-related chronic inflammation. In obesity, macrophages and adipocytes in VAT function as antigen-presenting cells and contribute to the obesity-specific CD4 T-cell response by inducing CD4 T-cell proliferation and differentiation into inflammatory effectors via interactions between major histocompatibility complex class II and T-cell receptors. When obesity persists, prolonged stimulation by leptin and circulating free fatty acids, repetitive antigen stimulation, activating stress responses, and hypoxia induce exhaustion of CD4 T cells in VAT. T-cell exhaustion is characterized by restricted effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector and memory T cells. Moreover, obesity causes thymic regression, which may result in homeostatic proliferation of obesity-specific T-cell subsets due to changes in T-cell metabolism and gene expression in VAT. In addition to causing T-cell exhaustion, obesity also accelerates cellular senescence of CD4 T cells. Senescent CD4 T cells secrete osteopontin, which causes further VAT inflammation. The obesity-associated transformation of CD4 T cells remains a negative legacy even after weight loss, causing treatment resistance of obesity-related conditions. This review discusses the marked transformation of CD4 T cells in VAT and systemic organs as a consequence of obesity-related microenvironmental changes.

The Different Insulin-Sensitising and Anti-Inflammatory Effects of Palmitoleic Acid and Oleic Acid in a Prediabetes Model.

Introduction Monounsaturated fatty acids (MUFA) are understood to have therapeutic and preventive effects on chronic complications associated with type 2 diabetes mellitus (T2DM); however, there are differences between individual MUFAs. Although the effects of palmitoleic acid (POA) are still debated, POA can regulate glucose homeostasis, lipid metabolism, and cytokine production, thus improving metabolic disorders. In this study, we investigated and compared the metabolic effects of POA and oleic acid (OA) supplementation on glucose and lipid metabolism, insulin sensitivity, and inflammation in a prediabetic model, the hereditary hypertriglyceridemic rat (HHTg). HHTg rats exhibiting genetically determined hypertriglyceridemia, insulin resistance, and impaired glucose tolerance were fed a standard diet. POA and OA were each administered intragastrically at a dose of 100 mg/kg b.wt. for four weeks. Results Supplementation with both MUFAs significantly elevated insulin and glucagon levels, but only POA decreased nonfasting glucose. POA-treated rats showed elevated circulating NEFA associated with increased lipolysis, lipoprotein lipase gene expression, and fatty acid reesterification in visceral adipose tissue (VAT). The mechanism of improved insulin sensitivity of peripheral tissues (measured as insulin-stimulated lipogenesis and glycogenesis) in POA-treated HHTg rats could contribute increased circulating adiponectin and omentin levels together with elevated FADS1 gene expression in VAT. POA-supplemented rats exhibited markedly decreased proinflammatory cytokine production by VAT, which can alleviate chronic inflammation. OA-supplemented rats exhibited decreased arachidonic acid (AA) profiles and decreased proinflammatory AA-derived metabolites (20-HETE) in membrane phospholipids of peripheral tissues. Slightly increased FADS1 gene expression after OA along with increased adiponectin production by VAT was reflected in slightly ameliorated adipose tissue insulin sensitivity (increased insulin-stimulated lipogenesis). Conclusions Our results show that POA served as a lipokine, ameliorating insulin sensitivity in peripheral tissue and markedly modulating the metabolic activity of VAT including cytokine secretion. OA had a beneficial effect on lipid metabolism and improved inflammation by modulating AA metabolism.

2021 Canadian Surgery Forum: Virtual, online Sept. 21-24, 2021.

# 01. Design and validation of a unique endoscopy simulator using a commercial video game {#article-title-2} Procedural simulation has been shown to enhance early endoscopy training. In this proof of concept study, we aimed to show that a first-person shooter (FPS) video game with a novel in-house

Omentin-1 and its relationship with inflammatory factors in maternal plasma and visceral adipose tissue of women with gestational diabetes mellitus.

To investigate the association of omentin-1 and inflammatory factors in serum and visceral adipose tissue (VAT) of women with gestational diabetes mellitus (GDM) compared to normal pregnant (NP) subjects. Furthermore, to examine their correlation with maternal clinical characteristics. We compared 116 GDM women to 115 NP women, at the time of cesarean section. Circulating omentin-1 and pro-inflammatory (IL-1β, IL-6, TNF-α), and anti-inflammatory cytokines (IL-1RA, IL-10) were examined. Moreover, their mRNA expression in VAT, along with inflammatory factors involved in the NF-κB pathway (TLR2, TLR4, NF-κB, IKκB), were examined. Circulating omentin-1 (p = 0.022) was lower and circulating IL-1-β, IL-1RA, as well as IL-10 (p = 0.005, p = 0.007, and p = 0.015, respectively), were higher in GDM compared to NP women. Omentin-1 correlated negatively with pre-pregnancy and gestational BMI, and HOMA-IR in all women, but was not associated with cytokines. TLR2, TLR4, IL-1β, IL-1RA, IL-6, IL-10 mRNA expression in VAT was lower in GDM compared with controls (p < 0.05 all). In multivariate analysis, BMI at delivery was significantly correlated to omentin-1 concentrations in all and NP subjects. In addition, omentin-1 expression was correlated to inflammatory gene expression in all, GDM and NP, women (p < 0.05 all). Serum levels and VAT gene expression of omentin-1 are not independently linked to GDM; notwithstanding, GDM women have a VAT-altered inflammatory status. In addition, no systemic association between omentin-1 and inflammatory factors was found, whereas associations between their expression in all women were observed, indicating that expression of these adipokines is linked between them regardless of GDM.

DAPAGLIFLOZIN, PIOGLITAZONE AND THEIR COMBINATION EFFECTED LEVELS OF LIPOPROTEINS AND ADIPOKINES IN PLASMA AND THEIR GENE EXPRESSION IN FAT IN RATS WITH DIABETES MELLITUS TYPE 1

Objective: Patients with diabetes mellitus type1 (DM1) have a relative insulin deficiency with elevated triacylglycerides (TAG) production. Adipokines are important in fat distribution, inflammation, and endothelial function. Dapagliflozin (Dapa) and pioglitazone (Pio) are oral hypoglycemic drugs for the treatment of DM2. They have also pleiotropic effects on lipid profile and body weight. The effect of these drugs on lipoproteins and adipokines levels in DM1 is poorly understood. Design and method: DM1 in male Wistar rats was induced by a single dose of streptozotocin (STZ). Animals were then divided into five groups: Controls, diabetic animals (DM), DM treated with Dapa, DM treated with Pio, DM treated with combination DapaPio. Therapies were mixed in rat chow. Control and DM groups received standard chow. After 6 weeks of treatment serum glucose and lipid levels were determined. Visceral adipose tissue (VAT) gene expression of leptin (Lep), adiponectin (AdipoQ), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL), tumor necrosis factor-alpha (TNFa) and interleukin 6 (IL6) were measured by RT qPCR and their levels in plasma were determined by ELISA method. Results: STZ injection led to a significant increase in both fasting and postprandial glucose levels and all levels of lipoproteins except high-density lipoproteins (HDL), which were decreased. We also found decreased levels of Lep, AdipoQ, LPL, and IL6, and increased HSL and TNFa in plasma in DM group. These results were supported by the same significant changes in gene expression in VAT. A combination of DapaPio resulted in a significant decrease in serum levels of both glucose levels. Pio and DapaPio administration decreased TAG and total cholesterol and increased HDL. Lep, AdipoQ, LPL and IL6 plasma levels were increased, and HSL, TNFa were decreased after administration of Dapa, Pio and their combination. Both monotherapy and combination significantly modulated Lep, TNFa and IL6 gene expression in VAT. Conclusions: DM1 in rats influenced not only glucose levels but also lipoproteins and adipokines in plasma, which could be affected by Dapa, Pio and DapaPio. Therapy can also change the gene expression of Lep, AdipoQ, TNFa, and IL6 in adipose tissue in rats with DM1.

Brief high fat high sugar diet results in altered energy and fat metabolism during pregnancy in mice

During pregnancy several maternal adaptations occur in order to support the growing fetus which are further exacerbated by gestational diabetes mellitus (GDM). Previously we developed a mouse model of GDM, however we did not evaluate alterations to energy and fat metabolism. We have also shown that alterations in lipid metabolism are mediated by adrenomedullin (ADM) in normal and GDM pregnancies. Our objectives were: (1) evaluate energy and fat homeostasis in our GDM mouse model and (2) determine if ADM may play a role in these changes. Female mice were placed on either control (P-CD) or high fat, high sucrose diet (P-HFHS) 1 week prior to and throughout pregnancy. Mice were placed into comprehensive lab animal monitoring system (CLAMS) chambers throughout pregnancy. Visceral adipose tissue (VAT) was collected at d17.5 of pregnancy for analysis. Energy Expenditure was significantly increased (p < 0.05) in P-HFHS dams compared to all other groups. VAT ex-vivo lipolysis was increased (p < 0.05) in P-HFHS compared to P-CD dams. VAT gene expression of ADM receptors Crlr, Ramp2, and Ramp3 was increased (p < 0.05) in P-HFHS dams. ADM dose dependently increased ex vivo lipolysis. This data further validates our animal model of GDM and is usefulness in investigating the pathophysiology of GDM.

Association of plasma fatty acids pattern with omentin gene expression in human adipose tissues: A cross-sectional study

Background and aimsOmentin, as an adipokine, has been reported to improve insulin resistance and inflammation may be related to fatty acids (FAs). Plasma FAs can be used as biomarkers of dietary FAs and endogenous FA exposure. We aimed to evaluate the association between plasma FAs pattern and omentin gene expression in adipose tissue (AT). Methods and resultsVisceral and subcutaneous AT and fasting blood were gathered from 97 adults aged >18 years. Participants were already admitted to hospitals for elective abdominal surgery. Dietary intakes were assessed using a food frequency questionnaire. The relative omentin gene expression in visceral and subcutaneous AT was measured by Real-Time PCR and plasma FAs was determined by gas chromatography. The principal component analysis was performed to derive the FAs pattern from plasma individual FAs. Three patterns were derived from plasma FAs, 1) high de-novo lipogenesis (DNL), 2) high trans saturated fatty acids (SFA), and docosahexaenoic acid (trans-SFA/DHA), and 3) high long-chain SFA (LC-SFA). After adjustment for age, sex, and insulin concentration, only the LC-SFA pattern was associated with omentin gene expression in visceral AT (β = 2.25, P = 0.03). Other patterns were not associated with omentin gene expression in visceral and subcutaneous AT. ConclusionA pattern characterized by high levels of myristic acid (14:0), heptadecanoic acid (17:0), pentadecanoic acid (15:0), and Cis_heptadecanoic acid (17:1), which named LC-SFA was related to omentin gene expression in visceral AT.

Influence of prenatal stress on metabolic abnormalities induced by postnatal intake of a high-fat diet in BALB/c mice.

Prenatal insults during fetal development result in increased likelihood of developing chronic disease. Obesity, the biggest risk factor for the development of metabolic disease, is affected by several genetic and environmental factors. High-fat diet (HFD) consumption is usually linked with the development of obesity. The main goal of this study was to analyze the impact of the exposure to a HFD in prenatally stressed animals. For this purpose, we subjected pregnant BALB/c mice to restraint stress for 2 h a day between gestational day (GD) 14 and GD 21. Prenatally stressed and control offspring of both sexes were postnatally exposed to a HFD for 24 weeks. We found that prenatal stress (PS) per se produced disturbances in males such as increased total blood cholesterol and triglycerides, with a decrease in mRNA expression of sirtuin-1. When these animals were fed a HFD, we observed a rise in glucose and insulin levels and an increase in visceral adipose tissue gene expression of leptin, resistin, and interleukin-1 beta. Although females proved to be more resilient to PS consequences, when they were fed a HFD, they showed significant metabolic impairment. In addition to the changes observed in males, females also presented an increase in body weight and adiposity and a rise in cholesterol levels.

Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat

ObjectivesEvidence suggests that visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) should be considered as distinct types of white fat. Although VAT plays a key role in metabolic syndrome (MetS), the role of subcutaneous adipose tissue (SAT) has been unclear. DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of MetS, develop adipocyte hypertrophy and inflammation to similar extents in SAT and VAT. We have now investigated the effects of salt loading and SAT removal on cardiac, renal, and VAT pathology in DS/obese rats.MethodsDS/obese rats were subjected to surgical removal of inguinal SAT or sham surgery at 8 weeks of age. They were provided with a 0.3% NaCl solution as drinking water or water alone for 4 weeks from 9 weeks of age.ResultsSalt loading exacerbated hypertension, insulin resistance, as well as left ventricular (LV) hypertrophy, inflammation, fibrosis, and diastolic dysfunction in DS/obese rats. It also reduced both SAT and VAT mass but aggravated inflammation only in VAT. Although SAT removal did not affect LV hypertrophy in salt-loaded DS/obese rats, it attenuated hypertension, insulin resistance, and LV injury as well as restored fat mass and alleviated inflammation and the downregulation of adiponectin gene expression in VAT. In addition, whereas salt loading worsened renal injury as well as upregulated the expression of renin–angiotensin-aldosterone system-related genes in the kidney, these effects were suppressed by removal of SAT.ConclusionsSAT removal attenuated salt-induced exacerbation of MetS and LV and renal pathology in DS/obese rats. These beneficial effects of SAT removal are likely attributable, at least in part, to inhibition of both VAT and systemic inflammation.

The Selective Peroxisome Proliferator-Activated Receptor Gamma Modulator CHS-131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis.

CHS‐131 is a selective peroxisome proliferator‐activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS‐131 on metabolic parameters and liver histopathology in a diet‐induced obese (DIO) and biopsy‐confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans‐fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy‐confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12‐13) to receive for the next 12 weeks (1) low‐dose CHS‐131 (10 mg/kg), (2) high‐dose CHS‐131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS‐131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO‐NASH mice with fibrosis. CHS‐131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS‐131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS‐131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO‐NASH mice treated with CHS‐131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS‐131 improves liver histology in a DIO and biopsy‐confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

OR20-02 Maternal Adiponectin Prevents Against Metabolic Dysfunction in Prenatally Androgenized PCOS-Like Mice

More than 10% of women worldwide are diagnosed with polycystic ovary syndrome (PCOS), causing reproductive and metabolic disease. Hyperandrogenism is the main characteristic and elevated levels of androgens during pregnancy affect placenta function and fetal programming, which leads to reproductive and metabolic dysfunction in the offspring. Adiponectin secreted from adipose tissue improves whole-body metabolism, but its role during pregnancy is under explored. Adiponectin affects placental nutrient transport during pregnancy allowing for speculation that adiponectin can exert endocrine effects on the developing fetus. This study aims to investigate if, in prenatally androgenized (PNA) mice, adiponectin can prevent metabolic and reproductive dysfunction in female offspring. Adiponectin transgenic (APNtg) and wildtype (wt) female mice were mated with wt males, and received dihydrotestosterone or vehicle injections between gestational days 16.5-18.5 to induce a PCOS-like phenotype. The anogenital distance, a marker of in utero androgen exposure, was measured at 22 days of age, estrus cyclicity was recorded at 6 weeks of age, and metabolic measures were performed at 4 months of age.APNtg dams gave birth to significantly smaller offspring, independent of genotype, than wt dams. PNA increased f-insulin in all groups but insulin sensitivity was higher in wt mice from APNtg dams compared to wt mice from wt dams. Insulin resistance correlated with subcutaneous and visceral fat mass. PNA increased visceral fat % and adipocyte size in wt offspring from wt dams while wt and APNtg offspring from APNtg dams were protected against this effect. Visceral adipose tissue gene expression was unaltered in PNA wt offspring, regardless of the dam’s genotype, while APNtg offspring, regardless of PNA, had increased expression of adipogenic genes. Anogenital distance was increased in all PNA wt offspring independent of the dam’s genotype. There was, however, no difference between APNtg-vehicle and APNtg-PNA mice, suggesting that adiponectin overexpression protects against this effect. PNA leads to disrupted estrous cycle and fewer ovulations, but this effect was less pronounced in PNA wt mice from APNtg dams. Our data suggests that elevated maternal adiponectin protects the offspring against PNA induced metabolic dysfunction, and to a lesser extent reproductive dysfunction.

Long-term hypercortisolism induces lipogenesis promoting palmitic acid accumulation and inflammation in visceral adipose tissue compared with HFD-induced obesity.

Glucocorticoids (GCs) play critical roles in adipose tissue metabolism. Here, we compare in a mouse model the effects of chronic glucocorticoid excess and diet-induced obesity on white adipose tissue mass and distribution, by focusing on visceral adipose tissue (VAT) fatty acid composition changes, the role of de novo lipogenesis (DNL) and the inflammatory state. We used a noninvasive mouse model of hypercortisolism to compare GC-induced effects on adipose tissue with diet-induced obesity [high-fat diet (HFD) 45%] and control mice after 10 wk of treatment. Subcutaneous adipose tissue (SAT) and VAT mass and distribution were measured by nuclear magnetic resonance imaging (NMRI). Fatty acid composition in VAT was analyzed by NMR spectroscopy and gas chromatography. Gene expression of key enzymes involved in DNL was analyzed in liver and VAT. Macrophage infiltration markers and proinflammatory cytokines were measured by gene expression in VAT. HFD or GC treatment induced similar fat mass expansion with comparable distribution between SAT and VAT depots. However, in VAT, GCs induce DNL, higher palmitic acid (PA), macrophage infiltration, and proinflammatory cytokine levels, accompanied by systemic nonesterified fatty acid (NEFA) elevation, hyperinsulinemia, and higher homeostatic model assessment for insulin resistance (HOMA-IR) levels compared with diet-induced obesity. Thus, chronic hypercortisolism induces DNL and fatty acid composition changes toward increased SFA and reduced polyunsaturated fatty acid (PUFA) levels in VAT, promoting macrophage recruitment and proinflammatory cytokines, suggesting a worse cardiometabolic profile even compared with HFD mice.

Interaction of HSD11B1 and H6PD polymorphisms in subjects with type 2 diabetes are protective factors against obesity: a cross-sectional study

BackgroundThe enzyme 11-beta hydroxysteroid dehydrogenase type 1 (HSD11B1) converts inactive cortisone to active cortisol in a process mediated by the enzyme hexose-6-phosphate dehydrogenase (H6PD). The generation of cortisol from this reaction may increase intra-abdominal cortisol levels and contribute to the physiopathogenesis of obesity and metabolic syndrome (MetS). The relationship of HSD11B1 rs45487298 and H6PD rs6688832 polymorphisms with obesity and MetS was studied. We also studied how HSD11B1 abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) gene expression is related to body fat distribution.MethodsRates of obesity and MetS features were cross-sectionally analyzed according to these polymorphisms in 1006 Brazilian white patients with type 2 diabetes (T2DM). Additionally, HSD11B1 expression was analyzed in VAT and SAT in a different cohort of 28 participants with and without obesity who underwent elective abdominal operations.ResultsAlthough polymorphisms of the two genes were not individually associated with MetS features, a synergistic effect was observed between both. Carriers of at least three minor alleles exhibited lower BMI compared to those with two or fewer minor alleles adjusting for gender and age (27.4 ± 4.9 vs. 29.3 ± 5.3 kg/m2; P = 0.005; mean ± SD). Obesity frequency was also lower in the first group (24.4% vs. 41.6%, OR = 0.43, 95% CI 0.21–0.87; P = 0.019). In the second cohort of 28 subjects, HSD11B1 gene expression in VAT was inversely correlated with BMI (r = − 0.435, P = 0.034), waist circumference (r = − 0.584, P = 0.003) and waist-to-height ratio (r = − 0.526, P = 0.010).ConclusionsThese polymorphisms might interact in the protection against obesity in T2DM individuals. Obese individuals may have decreased intra-abdominal VAT HSD11B1 gene expression resulting in decreasing intra-abdominal cortisol levels as a compensatory mechanism against central and general adiposity.

Adiponectin expression in visceral adiposity is an important determinant of insulin resistance in morbid obesity.

Visceral adiposity is associated with decreased serum adiponectin levels, peripheral resistance to insulin and an increased risk of cardio-metabolic complications. However, the link between adiponectin expression in visceral adipose tissue (VAT), its serum levels and metabolic protection is controversial. The aim of this study was to investigate the relationship between the adiponectin gene expression in VAT and clinical and metabolic parameters in patients with severe obesity. This is a cross-sectional study that included 51 severely obese patients (age 43.24±11.29 years, BMI 45.13±8.67 kg/m2), extensively evaluated clinically and biologically (metabolic tests, serum adiponectin measurements, HOMA-IR) before bariatric surgery. Omental adipose tissue was sampled during the intervention and the relative quantification of adiponectin gene expression was performed by real-time PCR, using beta-actin as reference gene. Adiponectin mRNA in VAT was significantly higher in obese insulin-sensitive patients than in the rest of obese patients (p < 0.05) and negatively correlated with HOMA-IR (r =-0.354, p=0.016) and uric acid (r =-0.304, p=0.045). After adjustment for gender, TG/HDL ratio and uric acid, adiponectin expresion (β= -0.439, p=0.001), waist circumference (β=0.467, p=0.001) and serum adiponectin (β =-0.339, p=0.011) remained significantly associated with HOMA-IR, together explaining more than 50% of its variation. In severely obese patients, adiponectin gene expression in VAT is negatively correlated with serum levels of uric acid and is an independent determinant, together with anthropometric parameters of visceral obesity and serum adiponectin levels, of insulin resistance.

Intrinsic aerobic capacity governs the associations between gut microbiota composition and fat metabolism age-dependently in rat siblings.

Host genetic factors affecting the gut microbiome play an important role in obesity, yet limited attention has been paid on the host genetic factors linked to physical fitness in modifying the microbiome. This study determined whether sibling-matched pairs of rats selectively bred for high (HCR) and low (LCR) aerobic capacity differ in their microbiome age-dependently and which taxa associate with differential in metabolism. Several taxa in young adult rats (hereafter young) linked to inherited aerobic capacity, while in older adult (hereafter old) rats most of the differences between the lines associated with body weight. Despite the absence of weight differential between LCR and HCR when young, the LCR microbiome contained more Actinobacteria, Veillonellaceae, Coriobacteriaceae, Phascolarctobacterium, and Ruminococcus; taxa previously linked to obesity. This raises the question whether the microbiome contributes to the later development of obesity in LCR. Age-related differences were detected in almost all taxa in both rat lines. The young HCR measured higher for serum glycerol and free fatty-acids and lower for cholesterol, HDL, LDL, and triglycerides than LCR. The old HCR differed from the old LCR by lower LDL. Several metabolites, including LDL, are associated age and genetic background-dependently with the microbiome, which might explain the metabolic differences between the lines. While old lines did not differ in visceral adipose tissue gene expression, the young HCR expressed more inflammatory genes than LCR, and several taxa including Proteobacteria associated with these genes. In conclusion, intrinsic aerobic capacity governs the microbiome, which may influence body weight, metabolism, and gene expression.

Serum vascular cell adhesion molecule-1 predicts significant liver fibrosis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with obesity, dyslipidemia and insulin resistance. NAFLD often presents as simple steatosis (NAFL) but can progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Current non-invasive biomarkers are not tailored to identify significant (⩾F2) fibrosis, although recent guidelines recommend a stringent follow-up of this patient population. We and others have reported on the role of pathological angiogenesis in the pathogenesis of NAFLD, highlighting pro-angiogenic factors as potential diagnostic markers. To investigate the applicability of angiogenic and endothelial dysfunction markers as non-invasive diagnostic tools for NASH or NASH-associated fibrosis in obese patients. In a prospective cross-sectional study, male patients undergoing bariatric surgery (n=61) and control patients (n=35) were recruited. Serum protein levels and visceral adipose tissue gene expression of endothelial dysfunction and angiogenic markers were analyzed by multiplex bead-based assay and quantitative RT-PCR, respectively. For validation, we recruited a second cohort of patients undergoing bariatric surgery (n=40) and a cohort of NAFLD patients from our outpatient clinic (n=30). We identified serum vascular cell adhesion molecule-1 (VCAM-1) as an independent predictor for ⩾F2 fibrosis (median 14.0 vs 8.7 ng ml-1 in patients with and without significant fibrosis; P<0.0001) with an area under the receiver-operating characteristics (AUROC) curve of 0.80. The cutoff point of 13.2 ng ml-1 showed a sensitivity of 80% and specificity of 83%. In line with these results, VCAM-1 visceral adipose tissue gene expression was also elevated in patients with fibrosis (P=0.030). In the bariatric surgery and clinical validation cohorts, VCAM-1 displayed similar AUROCs of 0.89 and 0.85, respectively. VCAM-1 levels are able to accurately predict significant (⩾F2) fibrosis in NAFLD patients.

Adipose Recruitment and Activation of Plasmacytoid Dendritic Cells Fuel Metaflammation

In obese individuals, visceral adipose tissue (VAT) is the seat of chronic low-grade inflammation (metaflammation), but the mechanistic link between increased adiposity and metaflammation largely remains unclear. In obese individuals, deregulation of a specific adipokine, chemerin, contributes to innate initiation of metaflammation by recruiting circulating plasmacytoid dendritic cells (pDCs) into VAT through chemokine-like receptor 1 (CMKLR1). Adipose tissue-derived high-mobility group B1 (HMGB1) protein activates Toll-like receptor 9 (TLR9) in the adipose-recruited pDCs by transporting extracellular DNA through receptor for advanced glycation end products (RAGE) and induces production of type I interferons (IFNs). Type I IFNs in turn help in proinflammatory polarization of adipose-resident macrophages. IFN signature gene expression in VAT correlates with both adipose tissue and systemic insulin resistance (IR) in obese individuals, which is represented by ADIPO-IR and HOMA2-IR, respectively, and defines two subgroups with different susceptibility to IR. Thus, this study reveals a pathway that drives adipose tissue inflammation and consequent IR in obesity.

PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial.

Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients. To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs). Randomized, double-blind, placebo-controlled study in type 2 diabetes. A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected. Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT. Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile. Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.