ADCY5 Gene Expression in Adipose Tissue Is Related to Obesity in Men and Mice

Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 gene—encoding adenylate cyclase 5—with increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk.     

Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome

Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21–25 kg/m²; n = 21) and morbidly obese women (BMI >40 kg/m²; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.     

Brown Adipose Tissue Activation Is Inversely Related to Central Obesity and Metabolic Parameters in Adult Human

Background

Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in affecting obesity. However, the supporting evidence on the relationship between BAT and central obesity and metabolic profile in large population based studies is sparse.

Methodology/Principal Findings

We studied 4011 (2688 males and 1323 females) tumor-free Chinese adults aged 18-89 for BAT activities, visceral/subcutaneous fat areas (VFA/SFA), waist circumferences (WC) and metabolic parameters. We found that the prevalence of BAT was around 2.7% in our study participants, with a significant sexual difference (5.5% in the females vs. 1.3% in the males; p<0.0001). BAT detection was increased in low temperature and declined in elderly subjects. The BAT positive subjects had lower BMI (P<0.0001), less SFA (P<0.01), VFA (P<0.0001), WC (P<0.0001), lower fasting glucose and triglyceride levels (both P<0.01) and increased HDL cholesterol concentrations (P<0.0001), compared with the BAT negative subjects. Robust logistic regression revealed that after adjustment for covariates (including age, sex, BMI, VFA, SFA and WC), age and BMI in the males (0.92 [95%CI, 0.88-0.96] and 0.84 [95% CI, 0.75-0.96], both P ≤0.008) while age and VFA in the females (0.87 [95%CI, 0.83-0.91] and 0.98 [95%CI, 0.97-0.99], respectively, P<0.05) were independently associated with detectable BAT.

Conclusions/Significance

Our data suggest that decreased amount of active BAT might be associated with accumulation of visceral fat content and unfavorable metabolic outcomes.     

The KRAB Zinc Finger Protein RSL1 Modulates Sex-Biased Gene Expression in Liver and Adipose Tissue To Maintain Metabolic Homeostasis

Krüppel-associated box zinc finger proteins (KRAB-ZFPs) are a huge family of vertebrate-specific repressors that modify gene expression in an epigenetic manner. Despite a well-defined repression mechanism, few biological roles or gene targets of KRAB-ZFP are known. Regulator of sex-limitation 1 (RSL1) is a mouse KRAB-ZFP that enforces male-predominant expression in the liver, affecting body mass and pubertal timing. Here we show that female but not male Rsl1^−/− mice gain more weight than wild-type mice on a high-fat diet (HFD) and that key liver and white adipose tissue (WAT) metabolic genes are altered in both Rsl1^−/− sexes in response to dietary stress. Expression profiling of Rsl1-sensitive genes in liver and WAT indicates that RSL1 accentuates sex-biased gene expression in liver but greatly diminishes it in WAT. RSL1 expression solely in liver is sufficient to limit diet-induced weight gain and suppress lipogenic genes in WAT, indicating that RSL1 balances metabolism via liver-to-adipose-tissue communication. RSL1''s effects on adult physiology exemplify a significant modulatory capacity of KRAB-ZFPs, in the absence of which there is widespread metabolic dysregulation. This ability to buffer against gene expression noise, coupled with extensive individual genetic variation, highlights the enormous potential of KRAB-Zfp genes as candidate risk factors for complex diseases.     

褐色脂肪组织代谢与肥胖

肥胖是由于机体能量储存与消耗的失衡而产生的.褐色脂肪组织通过产热的形式,能够将体内过多的能量释放出来,以减少能量积累,避免造成肥胖.现从褐色脂肪组织的结构、分布、功能以及调控机制等方面,对褐色脂肪组织与肥胖症的关系作一综述,旨在为防治肥胖症及相关疾病寻找理论基础和实验依据.     

GLUT4 Defects in Adipose Tissue Are Early Signs of Metabolic Alterations in Alms1GT/GT,a Mouse Model for Obesity and Insulin Resistance

Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alström Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alström mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alström mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.     

Visfatin mRNA在PCOS患者网膜脂肪组织中的表达

目的：探讨visfatin基因在多囊卵巢综合征（PCOS）网膜脂肪组织中的表达及相关影响因素。方法：采用半定量RT-PCR方法检测PCOS组（30例）和对照组（25例）网膜脂肪组织visfatin mRNA表达,并测量体重指数、腰臀比、空腹血糖、空腹胰岛素、胰岛素抵抗指数和血清性激素水平。结果：①PCOS组网膜脂肪组织visfatin mRNA表达量高于对照组（P=0.000）。②网膜脂肪组织visfatin mRNA的表达量与BMI、WHR、FINS、HOMA-IR呈正相关（P〈0.05）。③多元逐步回归分析显示,HOMA-IR（P=0.000）和WHR（P=0.005）是影响网膜脂肪组织visfatin mRNA表达的相关因素。结论：网膜脂肪组织visfatin mRNA表达可能与PCOS胰岛素抵抗的发生和肥胖相关。     

Rhein Protects against Obesity and Related Metabolic Disorders through Liver X Receptor-Mediated Uncoupling Protein 1 Upregulation in Brown Adipose Tissue

Liver X receptors (LXRs) play important roles in regulating cholesterol homeostasis, and lipid and energy metabolism. Therefore, LXR ligands could be used for the management of metabolic disorders. We evaluated rhein, a natural compound from Rheum palmatum L., as an antagonist for LXRs and investigated its anti-obesity mechanism in high-fat diet-fed mice. Surface plasmon resonance assays were performed to examine the direct binding of rhein to LXRs. LXR target gene expression was assessed in 3T3-L1 adipocytes and HepG2 hepatic cells in vitro. C57BL/6J mice fed a high-fat diet were orally administered with rhein for 4 weeks, and then the expression levels of LXR-related genes were analyzed. Rhein bound directly to LXRs. The expression levels of LXR target genes were suppressed by rhein in 3T3-L1 and HepG2 cells. In white adipose tissue, muscle and liver, rhein reprogrammed the expression of LXR target genes related to adipogenesis and cholesterol metabolism. Rhein activated uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) in wild-type mice, but did not affect UCP1 expression in LXR knockout mice. In HIB-1B brown adipocytes, rhein activated the UCP1 gene by antagonizing the repressive effect of LXR on UCP1 expression. This study suggests that rhein may protect against obesity and related metabolic disorders through LXR antagonism and regulation of UCP1 expression in BAT.     

Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity

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Inflammatory Cytokine Gene Expression in Mesenteric Adipose Tissue during Acute Experimental Colitis

Background

Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT.

Methods

Experimental colitis was induced in 6-month-old C57BL/6 mice by administration of dextran sulfate sodium (2% in drinking water) for up to 5 days. The induction of cytokine mRNA within various adipose tissues, including mesenteric, epididymal, and subcutaneous, was analyzed by qRT-PCR. These adipose tissues were also examined for histological evidence of inflammation. The level of cytokine mRNA during acute colitis was compared between mature mesenteric adipocytes, mesenteric stromal vascular fraction (SVF), and mesenteric lymph nodes.

Results

During acute colitis, MAT exhibited an increased presence of infiltrating mononuclear cells and fibrotic structures, as well as decreased adipocyte size. The mRNA levels of TNF-α, IL-1β, and IL-6 were significantly increased in MAT but not other adipose tissue depots. Within the MAT, induction of these cytokines was observed mainly in the SVF.

Conclusions

Acute experimental colitis causes a strong site-specific inflammatory response within MAT, which is mediated by cells of the SVF, rather than mature adipocytes or mesenteric lymph nodes.     

Decrease of the Obese Gene Expression in Bovine Subcutaneous Adipose Tissue by Fasting

The expression of mRNA of leptin, the product of the obese gene, in bovine adipose tissue was analyzed by a lysate RNase protection assay. The mRNA level was significantly decreased by food deprivation for two days and partially recovered after 3 hr of refeeding, indicating that obese gene expression in the ruminant was regulated by feeding.     

Uric Acid Secretion from Adipose Tissue and Its Increase in Obesity

Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.     

Genetic Analysis of Brown Adipose Tissue, Obesity and Growth in Mice

The hypothesis developed from single-gene mutant obese rodents that brown adipose tissue (BAT), through its thermogenic ability, is an important factor in the development of obesity, was tested in a randombred population of mice in which degree of adiposity is polygenically determined. Additive direct genetic parameters for measures of body size, lean, fatness and BAT at 6 wk of age were estimated under control and high-fat postweaning dietary regimens. Heritabilities were generally similar for the two diets. However, the lipid-free dry (LFD) component of BAT had a heritability estimate of 0.70 ± 0.26 on the control diet, but only 0.09 ± 0.20 on the high-fat diet. For all traits, genotype by diet interactions indicated that additive direct genetic rankings were not significantly different for the two diets. Based on estimates of genetic parameters in the control diet, selection for 6-wk body weight or 3- to 6-wk gain is expected to increase body size and adiposity. Selection for BAT weight is predicted to result in large, lean individuals. However, selection for the LFD content of BAT, generally believed to be a better indicator of thermogenic ability, is predicted to increase fatness as well as body size. Selection for LFD as a proportion of 6-wk body weight reduced the expected correlated response in fatness. It was concluded that BAT does not play a major role in determining the correlated response in obesity that is often found in populations selected for large body size.