The <em>Fabp4</em>-Cre-model is insufficient to study <em>Hoxc9</em> function in adipose tissue.

Developmental genes are important regulators of fat distribution and adipose tissue (AT) function. In humans, the expression of homeobox c9 (HOXC9) is significantly higher in subcutaneous compared to omental AT and correlates with body fat mass. To gain more mechanistic insights into the role of Hoxc9in AT, we generated Fabp4-Cre-mediated Hoxc9 knockout mice (ATHoxc9(-/-)). Male and female AT Hoxc9(-/-)mice were studied together with littermate controls both under chow diet (CD) and high-fat diet (HFD) conditions. Under HFD, only male ATHoxc9(-/-)mice gained less body weight and exhibited improved glucose tolerance. In both male and female mice, body weight, as well as the parameters of glucose metabolism and AT function were not significantly different between ATHoxc9(-/-) and littermate control CD fed mice. We found that crossing Hoxc9 floxed mice with Fabp4-Cre mice did not produce a biologically relevant ablation of Hoxc9in AT. However, we hypothesized that even subtle reductions of the generally low AT Hoxc9 expression may cause the leaner and metabolically healthier phenotype of male HFD-challenged AT Hoxc9(-/-)mice. Different models of in vitro adipogenesis revealed that Hoxc9 expression precedes the expression of Fabp4, suggesting that ablation of Hoxc9 expression in AT needs to be achieved by targeting earlier stages of AT development

Endocannabinoid receptors gene expression in morbidly obese with non alcoholic fatty liver disease

10.1155/2014/502542Background. Recent reports suggest a role for the endocannabinoid system in the pathology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the relationship between liver expression of cannabinoid (CB) receptor subtypes, CB1 and CB2, in morbidly obese (MO) women with different histological stages of NAFLD. Methods. We analysed hepatic CB1 and CB2 mRNA expression, and the expression of genes involved in lipid metabolism in 72 MO women, subclassified by liver histology into MO with normal liver (NL, n=16), simple steatosis (SS, n=28), and nonalcoholic steatohepatitis (NASH, n=28) by enzyme-linked immunosorbent assay and RT-PCR. Results. We found that CB1 mRNA expression was significantly higher in NASH compared with SS and correlated negatively with PPARa. Regarding CB2, CB2 mRNA expression correlated positively with ACC1, PPAR?, IL6, TNFa, resistin, and adiponectin. Conclusions. The increased expression of CB1 in NASH and the negative correlation with PPARa suggest a deleterious role of CB1 in NAFLD. Regarding CB2, its positive correlation with the anti-inflammatory molecule adiponectin and, paradoxically, with inflammatory genes suggests that this receptor has a dual role. Taken together, our results suggest that endocannabinoid receptors might be involved in the pathogenesis of NAFLD, a finding which justifies further study

Adipsin serum concentrations and adipose tissue expression in people with obesity and type 2 diabetes.

(1) Adipsin is an adipokine that may link increased fat mass and adipose tissue dysfunction to obesity-related cardiometabolic diseases. Here, we investigated whether adipsin serum concentrations and adipose tissue (AT) adipsin mRNA expression are related to parameters of AT function, obesity and type 2 diabetes (T2D). (2) Methods: A cohort of 637 individuals with a wide range of age and body weight (Age: 18–85 years; BMI: 19–70 kg/m2 ) with (n = 237) or without (n = 400) T2D was analyzed for serum adipsin concentrations by ELISA and visceral (VAT) and subcutaneous (SAT) adipsin mRNA expression by RT-PCR. (3) Results: Adipsin serum concentrations were significantly higher in patients with T2D compared to normoglycemic individuals. We found significant positive univariate relationships of adipsin serum concentrations with age (r = 0.282, p &lt; 0.001), body weight (r = 0.264, p&lt;0.001), fasting plasma glucose (r = 0.136, p = 0.006) and leptin serum concentrations (r = 0.362, p &lt; 0.001). Neither VAT nor SAT adipsin mRNA expression correlated with adipsin serum concentrations after adjusting for age, sex and BMI. Independent of T2D status, we found significantly higher adipsin expression in SAT compared to VAT (4) Conclusions: Our data suggest that adipsin serum concentrations are strongly related to obesity and age. However, neither circulating adipsin nor adipsin AT expression reflects parameters of impaired glucose or lipid metabolism in patients with obesity with or without T2D

Adipocytokine levels in women with anorexia nervosa. Relationship with weight restoration and disease duration

10.1002/eat.22166Objective: Starvation-induced depletion of fat stores in anorexia nervosa (AN) is known to be accompanied by alterations in some circulating adipocytokines. We analyzed a panel of circulating adipocytokines in women with AN compared with normal-weight controls and their relation with the disease duration and weight restoration. Method: We analyzed circulating adipocytokine levels in 28 patients with AN and in 33 normal-weight controls who were eating healthily. We determined by enzyme-linked immunosorbent assay the circulating levels of total and high molecular weight (HMW) adiponectin, lipocalin-2 (LCN2), leptin, tumor necrosis factor receptor-II (TNFRII), interleukin-6 (IL6), adipocyte fatty acid binding protein-4 (FABP4), ghrelin, and resistin. Results: The two circulating forms of adiponectin are higher in AN women compared with controls. Both total and HMW adiponectin related negatively to the duration of the disease (r52 0.372, p5 0.033; r52 0.450, p5 0.038, respectively). Furthermore, the lipid binding-proteins LCN2 and FABP4 are lower in AN compared to the control group. Finally, leptin levels are lower in AN against controls and correlated positively with disease duration (r5 0.537, p5 0.007). Resistin, ghrelin, TNFRII, and IL6 have similar values in both groups, although TNFRII and ghrelin related negatively to body mass index variation at the end of treatment (r52 0.456, p5 0.039; r52 0.536, p5 0.015, respectively). Discussion: These results suggest there is a need to investigate if changes in adipocytokine levels could serve as weight restoration biomarkers. Further studies are warranted to elucidate the specific role of these molecules in the timing of weight restoration

Metabolic effects of the waist-to-hip ratio associated locus <em>GRB14/COBLL1 </em>are related to <em>GRB14</em> expression in adipose tissue.

GRB14/COBLL1 locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that GRB14/COBLL1 may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), and that they may be regulated by SNP to effect obesity-related metabolic traits. We genotyped rs10195252 and rs6738627 in 2860 subjects with metabolic phenotypes. In a subgroup of 560 subjects, we analyzed GRB14/COBLL1 gene expression in paired visceral and subcutaneous adipose tissue (AT) samples. Mediation analyses were used to determine the causal relationship between SNPs, AT GRB14/COBLL1 mRNA expression, and obesity-related traits. In vitro gene knockdown of Grb14/Cobll1 was used to test their role in adipogenesis. Both gene expressions in AT are correlated with waist circumference. Visceral GRB14 mRNA expression is associated with FPG and HbA1c. Both SNPs are associated with triglycerides, FPG, and leptin levels. Rs10195252 is associated with HbA1c and seems to be mediated by visceral AT GRB14 mRNA expression. Our data support the role of the GRB14/COBLL1 gene expression in body FD and its locus in metabolic sequelae: in particular, lipid metabolism and glucose homeostasis, which is likely mediated by AT GRB14 transcript levels

Clinical and adipocytokine changes after bariatric surgery in morbidly obese women

10.1002/oby.20470Recent studies report the effect of bariatric surgery on glycaemia control and prevention of type-2-diabetes in obese patients. This study is about the pathophysiological mechanisms associated to these changes. DESIGN AND METHODS: Circulating levels of receptors of tumor necrosis factor (TNF-RI, TNF-RII), visfatin, high molecular weight (HMW) adiponectin, and C reactive protein (CRP) in 30 morbidly obese women (body mass index, BMI&amp;gt;40 kg/m(2) ) and 60 normal-weight controls (BMI&amp;gt;25 kg/m(2) ) were analyzed. Morbidly obese were studied at three time-points: before surgery (baseline), and 6 and 12 months after. RESULTS: After surgery, the levels of TNF-RI, TNF-RII, visfatin, and CRP were significantly lower than its baseline levels, whereas HMW adiponectin was higher. Fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA2-IR) levels were markedly lower postoperatively. High density lipoproteins (HDL) moderately increased, and triglyceride levels had sharply decreased. The study of the predictive value of variables indicated that preoperative levels of TNF-RI and visfatin correlated positively with levels of glucose, insulin, glycosylated hemoglobin A1c, and HOMA2-IR postoperatively, whereas adiponectin levels correlated negatively. Baseline CRP levels negatively linked to HDL and TNF-RII positively to triglyceride. CONCLUSIONS: The preoperative profile with high levels of proinflammatory adipocytokines is linked to smaller improvements in glucose homeostasis and lipid factors. The use of a range of biomarkers may predict the level of metabolic changes following bariatric surgery

Associations between markers of childhood body composition and type 2 diabetes in adulthood

Background and aims: Glimepiride is a third generation sulfonylurea drug, used to stimulate insulin secretion in type II diabetic patients. Since the introduction of tolbutamide, decades of research have led to the development of compounds like glimepiride that improve the pharmacological effects and largely limit the side effects as hypoglycemia. The interaction of glimepiride with KATP channels, the bona fide target of sulfonylureas, cannot fully explain the differences in observed effects between glimepiride and earlier sulfonylureas. While screening a large library of compounds, we observed that glimepiride potentiates the activity of TRPM5. TRPM5 is a calcium-activated monovalent cation channel that is expressed in the pancreatic beta-cells where it is involved in the regulation of glucose-induced insulin secretion. Materials and methods: We examined the interaction between glimepiride and TRPM5 in a series of in vitro and in vivo experiments. For this aim we measured TRPM5 currents evoked by glimepiride in HEK-cells overexpressing TRPM5. We isolated pancreatic islets from WT, Trpm5-/-, and KATP functional pore mutant mice and measured the changes in intracellular calcium dynamics in the islets. Ultimately we analysed the effects of glimepiride in vivo. Results: Glimepiride increases TRPM5-mediated currents in HEK cells. In isolatedWTmouse pancreatic islets, we observe calcium activity in the presence of glimepiride in a lower concentration range compared to Trpm5-/- islets. Furthermore, islets form KATP pore-mutant mice, there is increased Ca2+ activity in the beta-cells upon glimpepiride application. Ultimately in Trpm5-/- mice, glimepiride has less antihyperglycemic effects after a glucose injection compared to WT mice, indicating TRPM5 has a role in the signal transduction of glimepiride in the beta-cells. Conclusion: The action on TRPM5 is downstream of increases in [Ca2+]i, and as such glucose-dependent. Therefore, our data suggest an explanation for the reduced hypoglycemic effect of glimepiride. Taken together, the promiscuity of glimepiride leads to synergetic action on TRPM5 and KATP channels to stimulate insulin secretion from pancreatic beta-cells. This new information confirms the hypothesis that targetingTRPM5is a valid approach to stimulate insulin secretion and in fact, is unknowingly already widely used.status: Published onlin