Gnas ablation in CD11c+ cells prevents high-fat diet-induced obesity by elevating adipose tissue catecholamine levels and thermogenesis

CD11c+ immune cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type 2 diabetes (T2D). In obesity, CD11c+ immune cells are recruited to white adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. In this study, we found that ablation of Gnas, the gene that encodes Gas, in CD11c expressing cells protects mice from high-fat diet-induced obesity, glucose intolerance and insulin resistance. GnasΔCD11c mice (KO) had increased oxygen consumption, energy expenditure, and beigeing of white adipose tissue (WAT). Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and the absence of T and B cells by crossing the KO to a Rag1-/- background did not alter the phenotype. Notably, we observed elevated norepinephrine and elevated cAMP signaling in the WAT of KO mice. The KO adipose tissue also had reduced expression of catecholamine transport and degradation enzymes. Collectively, our results identified an important role of Gas in CD11c+ cells in whole body metabolism regulation by controlling norepinephrine levels in WAT, modulating catecholamine-induced lipolysis and increasing thermogenesis that together created a lean phenotype.