. contributed equally to this manuscript. BACKGROUND AND PURPOSEGlucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic (T2D) patients and cause weight loss in obese subjects by as yet unknown mechanisms. We recently demonstrated that the GLP-1 receptor, which is present in adipocytes and the stromal vascular fraction of human adipose tissue (AT), is up-regulated in AT of insulin-resistant morbidly obese subjects compared with healthy lean subjects. The aim of this study was to explore the effects of in vitro and in vivo administration of GLP-1 and its analogues on AT and adipocyte functions from T2D morbidly obese subjects. EXPERIMENTAL APPROACHWe analysed the effects of GLP-1 on human AT and isolated adipocytes in vitro and the effects of GLP-1 mimetics on AT of morbidly obese T2D subjects in vivo. KEY RESULTSGLP-1 down-regulated the expression of lipogenic genes when administered during in vitro differentiation of human adipocytes from morbidly obese patients. GLP-1 also decreased the expression of adipogenic/lipogenic genes in AT explants and mature adipocytes, while increasing that of lipolytic markers and adiponectin. In 3T3-L1 adipocytes, GLP-1 decreased free cytosolic Ca 2+ concentration ([Ca 2+ ] i ). GLP-1-induced responses were only partially blocked by GLP-1 receptor antagonist exendin (9-39). Moreover, administration of exenatide or liraglutide reduced adipogenic and inflammatory marker mRNA in AT of T2D obese subjects. CONCLUSIONS AND IMPLICATIONSOur data suggest that the beneficial effects of GLP-1 are associated with changes in the adipogenic potential and ability of AT to expand, via activation of the canonical GLP-1 receptor and an additional, as yet unknown, receptor.Abbreviations ADRP, adipocyte differentiation-related protein; AT, adipose tissue; ATGL, adipose triglyceride lipase; BMI, body mass index; FABP4, fatty acid binding protein 4; FASN, fatty acid synthase; GLP-1, glucagon-like peptide-1; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; MO, morbidly obese; SAT, subcutaneous AT; SREBP1, sterol regulatory element-binding transcription factor 1; T2D, type 2 diabetic; VAT, visceral AT

Impaired adipose tissue (AT) lipid handling and inflammation is associated with obesity-related metabolic diseases. Circulating lipopolysaccharides (LPSs) from gut microbiota (metabolic endotoxemia), proposed as a triggering factor for the low-grade inflammation in obesity, might also be responsible for AT dysfunction. Nevertheless, this hypothesis has not been explored in human obesity. To analyze the relationship between metabolic endotoxemia and AT markers for lipogenesis, lipid handling, and inflammation in human obesity, 33 patients with obesity scheduled for surgery were recruited and classified according to their LPS levels. Visceral and subcutaneous AT gene and protein expression were analyzed and adipocyte and AT in vitro assays performed. Subjects with obesity with a high degree of metabolic endotoxemia had lower expression of key genes for AT function and lipogenesis ( SREBP1, FABP4, FASN, and LEP) but higher expression of inflammatory genes in visceral and subcutaneous AT than subjects with low LPS levels. In vitro experiments corroborated that LPS are responsible for adipocyte and AT inflammation and downregulation of PPARG, SCD, FABP4, and LEP expression and LEP secretion. Thus, metabolic endotoxemia influences AT physiology in human obesity by decreasing the expression of factors involved in AT lipid handling and function as well as by increasing inflammation.