UC San Diego

Obesity is a common condition characterized by low-grade systemic inflammation that leads to comorbities such as insulin resistance. Overnutrition causes disturbance in metabolic homeostasis and causes gradual accumulation of CD11c+ cells to create an inflammatory state in adipose tissue. Our studies identified the ablation of Gnas gene which encodes for the stimulatory G-protein alpha subunit (Gαs) responsible for generation of cyclic AMP (cAMP), in CD11c+ cells protected mice from obesity-mediated inflammation and insulin resistance. The GnasΔCD11c mice (KO) maintained a lean phenotype when stressed with high-fat diet (HFD) and results showed improved insulin sensitivity and glucose tolerance. Histological analysis of white adipose tissue (eWAT) of KO mice on HFD showed reduced crown-like structures (CLS) whose formation is often associated with inflammasome activation in macrophages. To further investigate the reduced inflammatory status of KO mice, we cultured and stimulated CD11c+ bone-marrow derived macrophages (BMDM) to induce inflammasome activation. Notably, the inflammasome gene expression and pro-inflammatory cytokine secretion was significantly blunted. In addition, we found treating KO BMDM with cell-permeable cAMP analog restored the inflammasome-mediated inflammatory response. Collectively, our results demonstrate Gαs-cAMP signaling in CD11c+ cells play important roles in regulating high fat diet-induced immune responses in mice.