Visceral Adipose Tissue Expression Research Articles

Comparison of Gene Transcription between Subcutaneous and Visceral Adipose Tissue in Chinese Adults

Obese individuals with fat stored in visceral adipose tissue (VAT) generally suffer greater adverse metabolic consequences than those with fat stored predominantly in subcutaneous adipose tissue (SAT), but its molecular basis is not completely understood. We isolated paired samples of SAT and VAT from 15 lean and 15 obese subjects and systematically compared the transcription level of genes that may determine fat distribution and metabolic sequelae between SAT and VAT using quantitative real-time PCR. We found that, leptin levels were lower in VAT than SAT, for both lean and obese subjects. In lean subjects, tumor necrosis factor-alpha (TNF-alpha) was expressed equally in both fat depots, while toll-like receptor 4 (TLR4) and glucocorticoid receptor (GR) showed significantly lower expression in VAT than SAT. In obese subjects, TNF-alpha and TLR4 expression were significantly higher in VAT than SAT, yet GR expression did not differ in these areas. For all subjects, VAT 11beta-hydroxysteroid dehydrogenate type 1 (11beta-HSD1) level was significantly correlated with BMI. GR expression level was significantly correlated with TLR4 expression level. Cultured adipocytes showed higher TLR4 mRNA level after differentiation, and higher TNF-alpha level after treatment with free fatty acids. These results suggest that there are depot-specific differences in leptin, TNF-alpha, TLR4 and GR transcriptions in humans. TLR4 signaling and higher 11beta-HSD1 and GR levels in VAT may contribute predominantly to inflammatory factor production and subsequent metabolic sequelae in obese human.

Decreased lipin 1β expression in visceral adipose tissue is associated with insulin resistance in polycystic ovary syndrome

ObjectiveIn polycystic ovary syndrome (PCOS), insulin resistance (IR) appears with high prevalence and represents the major cause of cardiometabolic complications. Lipin 1β regulates lipid metabolism and augments insulin sensitivity. The impact of lipin 1β expression in visceral and subcutaneous adipose tissue of PCOS patients on IR was studied for the first time.MethodsEighty-five PCOS patients and 44 controls were enrolled for subcutaneous tissue biopsy, of whom 25 patients and 30 controls also underwent visceral adipose tissue biopsy. Gene expression of lipin 1β was measured, together with that of peroxisome proliferator-activated receptor γ, lipoprotein lipase, hormone-sensitive lipase, adiponectin and glucose transporter 4 in subcutaneous and visceral adipose tissue. Markers of obesity, IR and PCOS were also measured.ResultsIn PCOS patients, lipin 1β expression in both adipose depots was lower than in controls: 0.76 (0.67–0.84) vs 1.16 (0.90–1.43) for visceral and 0.91 (0.73–1.10) vs 1.30 (1.03–1.57) for s.c. depot (both P<10−4). The difference remained significant after adjustment for body mass index (BMI) and also when comparing only lean patients with lean controls. In PCOS patients, visceral adipose lipin 1β expression correlated negatively with homeostasis model assessment–IR (r=−0.474, P=0.017), BMI (r=−0.511, P=0.009) and waist circumference (r=−0.473, P=0.017), waist circumference remaining significant (P=0.027) in multiple regression. Subcutaneous lipin 1β expression in PCOS correlated negatively with BMI, waist circumference and plasma triglycerides, and positively with high density lipoprotein-cholesterol. Subcutaneous, but not visceral lipin 1β expression, correlated positively with the studied genes.ConclusionsLipin 1β appears to be involved in the pathogenesis of IR in PCOS.

11β-Hydroxysteroid Dehydrogenase Type 1 is Overexpressed in Subcutaneous Adipose Tissue of Morbidly Obese Patients

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme catalyzes interconversion of inactive cortisone to active cortisol. Its expression in adipose tissue has been associated with obesity and some of its metabolic disorders. Controversies regarding which fat depots [subcutaneous adipose tissue (SAT) or visceral adipose tissue (VAT)] have higher expression still remain. The aim of this work was to evaluate 11beta-HSD1 expression in SAT and VAT of obese patients and evaluate its association to metabolic features of metabolic syndrome. In 32 morbidly obese patients, paired samples of SAT and VAT were collected. All patients, 40.2+/-12.3 years and 36.7+/-3.8 body mass index (BMI), underwent sleeve gastrectomy or laparoscopic gastric bypass. Gene expression of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction. Spearman correlation test was used to evaluate relationships between 11beta-HSD1 levels and clinical and biochemical parameters. 11beta-HSD1 mRNA levels were higher in SAT than in VAT, with median expression levels of 11.4 arbitrary units (AU) and 7.8 AU, respectively (p=0.03). SAT 11beta-HSD1 mRNA were correlated with VAT mRNA levels (r=-0.6, p=0.018) and hip circumference (r=0.66, p=0.018). SAT 11beta-HSD1 levels increase parallel according to BMI category. We did not find a correlation between SAT or VAT with fasting glucose (r=0.15, p=NS), total cholesterol (r=0.13, p=NS), triglycerides (r=0.04, p=NS), and high-density lipoprotein (r=-0.16, p=NS). However, SAT expression in patients with features of MS was higher than those without features of MS. Our results demonstrate that SATs express higher 11beta-HSD1 mRNA levels than VAT. This finding highlights the importance of SAT in obesity and its possible role on metabolic disorders associated with obesity.

High‐fat Diet Alters PP2A, TC10, and CIP4 Expression in Visceral Adipose Tissue of Rats

The aim of this study was to investigate a possible link between high-fat diet (HFD)-induced obesity and the expression of protein phosphatase 2A (PP2A) and Cdc42-interacting protein 4 (CIP4) proteins, potential downstream components of the IRS/PI3K/AKT and CAP/Cbl/TC10 pathway, respectively, in the visceral adipose tissue. Twenty male Sprague-Dawley rats were randomly divided into two groups and were given either HFD or the normal diet (ND) for 8 weeks. The HFD-induced changes in the expression of the epididymal adipose tissue genes involved in the insulin-signaling pathways were evaluated using real-time reverse-transcription PCR and western blot analysis. The exposure of rats to HFD for 8 weeks resulted in a significant increase in the expression of PP2A at both the transcriptional and translational levels, along with a marked reduction in the levels of phosphorylated AKT and insulin receptor substrate-1 (IRS-1) in the cytosol of visceral adipocytes, compared with the ND rats. Besides, there were significant HFD-induced decreases in the mRNA and protein levels of CIP4 and TC10 in the adipose tissue of rats. These data suggest that HFD might have a relevance to insulin resistance by increasing the expression of PP2A, an inhibitor of AKT activity in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and also by suppressing the expression of TC10 and CIP4, downstream effectors of the Cbl/CAP/TC10 insulin-signaling cascade in the visceral adipose tissue.

Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect. We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat-fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14(-)(/)(-) mutant mice mimicked the metabolic and inflammatory effects of antibiotics. This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.

Birth weight and gender determine expression of adipogenic, lipogenic and adipokine genes in perirenal adipose tissue in the young adult sheep

Epidemiological studies have demonstrated that low birth weight is associated with an increased incidence of visceral obesity and metabolic disorders in later life. In the present study, we have determined the impact of birth weight and gender on gene expression in visceral adipose tissue (VAT) in the young adult sheep. Lambs ( n = 19, birth weight range 2.6–7.55 kg) were born at term and growth monitored for 22.4 ± 0.2 weeks, when body composition was determined by Dual X-ray Absorptiometry (DXA) and samples of VAT and subcutaneous (SCAT) adipose tissue collected. Plasma samples were collected at post-mortem for the determination of free fatty acids (FFA), glucose and insulin concentrations. Peroxisome-Proliferator Activated Receptor-γ (PPARγ), glycerol-3-phosphate dehydrogenase (G3PDH), lipoprotein lipase (LPL), adiponectin and leptin mRNA expression was determined by qRT-PCR. Fractional growth rate in postnatal weeks 1–3 was inversely related to birth weight in both males and females ( R 2 = 0.22, P < 0.05, n = 19). PPARγ mRNA expression in VAT, but not SCAT, was inversely related to birth weight ( R 2 = 0.60, P < 0.01, n = 18). In males, but not females, PPARγ mRNA in VAT was directly related to G3PDH mRNA expression ( R 2 = 0.69, P < 0.01, n = 9). Plasma FFA concentrations were inversely related to birth weight in both males and females ( R 2 = 0.22, P < 0.05, n = 19). These findings demonstrate that low birth weight is associated with an increased expression of a key adipogenic factor in visceral adipose tissue in young adulthood. In males, this is associated with an increased expression of lipogenic genes, and this may contribute to the increased propensity for visceral obesity in low birth weight males compared to females.

Inverse relationship between obesity and FTO gene expression in visceral adipose tissue in humans

Recently, FTO was identified as a candidate gene contributing to both childhood and severe adult obesity. We tested the hypothesis that mRNA expression of FTO and/or of the neighbouring RPGRIP1L in adipose tissue correlates with measures of obesity and fat distribution. We also investigated whether the FTO obesity risk alleles might explain variability in FTO and RPGRIP1L mRNA expression. In paired samples of visceral and subcutaneous adipose tissue from 55 lean and obese participants, we investigated whether FTO and RPGRIP1L mRNA expression is fat depot-specific, altered in obesity and related to measures of fat accumulation, insulin sensitivity and glucose metabolism. All participants were genotyped for the obesity-associated rs8050136 FTO variant. FTO mRNA expression was threefold higher in subcutaneous than in visceral adipose tissue. Subcutaneous FTO expression correlated with visceral FTO expression. FTO gene expression in both depots correlated with age and was negatively correlated to BMI and per cent body fat. FTO mRNA levels were not related to measures of insulin sensitivity and glucose metabolism. RPGRIP1L mRNA expression was 1.6-fold higher in visceral than in subcutaneous adipose tissue, but did not correlate with anthropometric and metabolic characteristics. There was no association between rs8050136 and FTO or RPGRIP1L mRNA expression in adipose tissue. Expression of adipose tissue FTO mRNA is fat depot-specific and negatively correlates with measures of obesity. However, the direction of this relationship still needs to be elucidated.

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

The beneficial metabolic actions of peroxisome proliferator-activated receptor gamma (PPARgamma) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This study aimed to assess the contribution of GC attenuation to PPARgamma agonism action on gene expression in visceral adipose tissue and global metabolic profile. Rats were treated (2 weeks) with the PPARgamma agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARgamma-mediated GC attenuation. mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. Whereas HiCORT did not alter RWAT mass, RSG increased the latter (+33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPARgamma agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORT-induced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. The GC and PPARgamma pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPARgamma agonism are retained under imposed high ambient GC, and are therefore independent from PPARgamma effects on 11beta-HSD1-mediated GC production.

Changes in Leptin Levels and its Association With Insulin

Obesity currently qualifies as a worldwide health epidemic. With the cloning of mouse ob gene and its receptor leptin was discovered. Leptin is expressed and secreted primarily by adipose tissue and is highly correlated to body fat mass. Nevertheless many factors can regulate leptin synthesis and expression, such as fasting, sympathetic activity, insulin, exercise and changes in energy balance. Endurance training effects on leptin are still contradictory. PURPOSE: To assess the effects of swimming training on leptin levels, the contribution of leptin expression in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and the association between leptin, insulin, body composition, basal metabolic rate and energy intake in rats. METHODS: Male Wistar rats were separated in two groups: trained and sedentary control. The exercised-trained group was submitted to 9 weeks of endurance swimming training. Body weight and food intake were recorded weekly. Oral glucose tolerance tests were performed before and during the last week of exercise training. Furthermore, basal metabolic rate, leptin and insulin levels, body fat mass and leptin expression in SAT and VAT were determined after training. RESUITS: Energy intake and basal energy expenditure were not different between groups. Trained rats had a 10% lower final body weight, 36% lower body fat mass, 55% lower insulin levels and improved glycemic response (p<0,05 for all variables). Although trained animals had lower leptin levels, no difference in leptin expression in either fat depot was found between groups. According to stepwise multiple regression analysis lower leptin levels in trained rats were due primarily to their lower body fat mass. Nonetheless, after adjustment for body fat mass leptin levels were still 28,6% (p<0,05) lower in exercised rats. CONCLUSIONS: We have found that 9 weeks of swimming training does not affect leptin expression, while leading to a decrease in leptin levels independently of changes in total body fat mass. Theses results suggest that there might be other factors rather than fat mass responsible for the decreased leptin levels found in trained animals, being insulin the primary candidate for such modulation role. Supported by Fapesp (04/03888-3)

Activation of Transient Receptor Potential Vanilloid Type-1 Channel Prevents Adipogenesis and Obesity

We tested the hypothesis that activation of transient receptor potential vanilloid type-1 (TRPV1) by capsaicin prevents adipogenesis. TRPV1 channels in 3T3-L1-preadipocytes and visceral adipose tissue from mice and humans were detected by immunoblotting and quantitative real-time RT-PCR. The effect of TRPV1 on cytosolic calcium was determined fluorometrically in 3T3-L1-preadipocytes and in human visceral fat tissue. Adipogenesis in stimulated 3T3-L1-preadipocytes was determined by oil red O-staining of intracellular lipid droplets, triglyceride levels, expression of peroxisome proliferator-activated receptor-gamma, and expression of fatty acid synthase. Long-term feeding experiments were undertaken in wild-type mice and TRPV1 knockout mice. We detected TRPV1 channels in 3T3-L1-preadipocytes and visceral adipose tissue from mice and humans. In vitro, the TRPV1 agonist capsaicin dose-dependently induced calcium influx and prevented the adipogenesis in stimulated 3T3-L1-preadipocytes. RNA interference knockdown of TRPV1 in 3T3-L1-preadipocytes attenuated capsaicin-induced calcium influx, and adipogenesis in stimulated 3T3-L1-preadipocytes was no longer prevented. During regular adipogenesis TRPV1 channels were downregulated which was accompanied by a significant and time-dependent reduction of calcium influx. Compared with lean counterparts in visceral adipose tissue from obese db/db and ob/ob mice, and from obese human male subjects we observed a reduced TRVP1 expression. The reduced TRPV1 expression in visceral adipose tissue from obese humans was accompanied by reduced capsaicin-induced calcium influx. The oral administration of capsaicin for 120 days prevented obesity in male wild type mice but not in TRPV1 knockout mice assigned to high fat diet. We conclude that the activation of TRPV1 channels by capsaicin prevented adipogenesis and obesity.

Human Adenovirus 36 Induces Adiposity, Increases Insulin Sensitivity, and Alters Hypothalamic Monoamines in Rats

Human adenovirus 36 (Ad-36) increases adiposity and reduces serum lipids in chicken, mouse, and non-human primate models, and it is linked to obesity in sero-epidemiological studies in humans. Involvement of the central nervous system (CNS) or adipose tissue in the mechanism of Ad-36-induced adiposity is unknown. The effects of Ad-36 on adiposity and on the neuroendocrine system were investigated in a rat model. Five-week-old male Wistar rats were inoculated intraperitoneally with Ad-36 or medium. Despite similar food intakes, infected rats attained significantly greater body weight and fat pad weight by 30 weeks post-inoculation. Epididymal-inguinal, retroperitoneal, and visceral fat pad weights of the infected group were greater by 60%, 46%, and 86%, respectively (p < 0.00001). The fasting serum insulin level and homeostasis model assessment index indicated greater insulin sensitivity in the infected group. Visceral adipose tissue expression of glycerol 3-phosphate dehydrogenase, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein alpha and beta was markedly increased in the infected animals compared with controls. Ad-36 decreased norepinephrine levels significantly in the paraventricular nucleus in infected vs. control rats (mean +/- standard error, 8.9 +/- 1.1 vs. 12.8 +/- 1.2 pg/microg protein; p < 0.05). Ad-36 markedly decreased serum corticosterone in infected vs. control rats (mean +/- standard error, 97 +/- 41.0 vs. 221 +/- 111 ng/mL; p < 0.005). The results suggest that the pro-adipogenic effect of Ad-36 may involve peripheral as well as central effects. The male Wistar rat is a good model for the elucidation of metabolic and molecular mechanisms of Ad-36-induced adiposity.

Dietary calcium regulates ROS production in aP2-agouti transgenic mice on high-fat/high-sucrose diets

We have previously demonstrated that 1alpha, 25(OH)2D3 promotes adipocyte reactive oxygen species (ROS) production. We have now evaluated whether decreasing 1alpha, 25(OH)2D3 levels by increasing dietary calcium will decrease oxidative stress in vivo. We fed low-calcium (0.4% Ca) and high-calcium (1.2% Ca from CaCO3) obesity-promoting (high sucrose/high fat) diets to aP2-agouti transgenic mice and assessed regulation of ROS production in adipose tissue and skeletal muscle. Mice on the high-calcium diet gained 50% of the body weight (P=0.04) and fat (P<0.001) as mice on the low-calcium diet (0.4% Ca). The high-calcium diet significantly reduced adipose intracellular ROS production by 64 and 18% (P<0.001) and inhibited adipose tissue nicotinamide adenine dinucleotide phosphate oxidase expression by 49% (P=0.012) and 63% (P=0.05) in visceral and subcutaneous adipose tissue, respectively. Adipocyte intracellular calcium ([Ca2+]i) levels were suppressed in mice on the high-calcium diet by 73-80% (P<0.001). The high-calcium diet also induced 367 and 191% increases in adipose mitochondrial uncoupling protein 2 (UCP2) expression (P<0.001) in visceral and subcutaneous adipose tissue, respectively. The pattern of UCP3 expression and indices of ROS production in skeletal muscle were consistent with those in adipose tissue. The high-calcium diet also suppressed 11beta-hydroxysteroid dehydrogenase (11beta-HSD) expression in visceral adipose tissue by 39% (P=0.034). 11beta-HSD expression was markedly higher in visceral vs subcutaneous adipose tissue in mice on the low-calcium diet (P=0.034), whereas no difference was observed between the fat depots in mice on the high-calcium diet. These data support a potential role for dietary calcium in the regulation of obesity-induced oxidative stress.

Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats

There is increasing evidence that poor early growth confers an increased risk of type 2 diabetes, hypertension, and other features of the metabolic syndrome in later life. We hypothesized that this may result from poor nutrition during early life exerting permanent effects on the structure and function of key metabolic organ systems. To study the long-term impact of early-life undernutrition on susceptibility to visceral adiposity, we used a rat model of maternal protein restriction (MPR) in which dams were fed a low-protein diet (containing 8% instead of 20% protein in control diet) throughout pregnancy and lactation. MPR offspring were born smaller than controls (offspring of dams on control diet) and in adulthood developed visceral adiposity. We compared the pattern of gene expression in visceral adipose tissue (VAT) between MPR offspring and controls with Affymetrix rat expression arrays. Of the total number of genes and expressed sequence tags analyzed (15,923 probe sets), 9,790 (61.5%) were expressed in VAT. We identified 650 transcripts as differentially expressed > or =1.5-fold in the VAT of MPR offspring. Gene ontology analysis revealed a global upregulation of genes involved in carbohydrate, lipid, and protein metabolism. A number of genes involved in adipocyte differentiation, angiogenesis, and extracellular matrix remodeling were also upregulated. However, in marked contrast to other rodent models of obesity, the expression of a large number of genes associated with inflammation was reduced in this rat model. Thus visceral adiposity in this early-life programmed rat model is marked by dynamic changes in the transcriptional profile of VAT. Our data provide new insights into the molecular mechanisms that underlie the early-life programming of visceral adiposity.

Subcutaneous or visceral adipose tissue expression of the PPARγ gene is not altered in the fatty ( [formula omitted]) Zucker rat

We cloned 537 basepairs (bp) of rat partial peroxisome proliferator-activated receptor γ2 (PPARγ2) cDNA and examined the effect of fasting or obesity on the expression of two isoforms of rat PPARγ, γ1 and γ2, in either subcutaneous or mesenteric adipose tissue specimens using an RNase A protection assay. In Wistar rats, expression of both isoforms was dramatically reduced after 48 hours of fasting in the two fat tissue specimens. In comparing genetically obese ( fa fa ) Zucker rats and lean control rats, no significant difference was observed in expression of the two isoforms in either type of adipose tissue. From these findings, we conclude that the adipose tissue level of rat PPARγ depends on nutritional deprivation but is not closely associated with either obesity or insulin resistance in obese Zucker rats.