1204-P: Antidiabetic Effects of GLP-1 Analogs Are Mediated by Il-6-Induced Adipocyte Beiging

Mechanisms underlying antidiabetic effects of incretins remain incompletely understood. We have discovered that GLP-1 analogs increase IL-6 secretion from leukocytes and, hence, IL-6 plasma levels in obese humans and mice. Based on the observation that IL-6 induces STAT3 phosphorylation in preadipocytes, we hypothesized that incretins may regulate adipose tissue (AT) function by IL-6-dependent control of white vs. beige adipogenesis. Here, we show that IL-6 promotes liraglutide-induced increase in UCP-1 expression in mouse preadipocytes. Two weeks of liraglutide therapy in mice raised on high-fat diet (HFD) resulted in a reduced adiposity, increased AT beiging, increased cold tolerance and better glucose control, compared to untreated mice. Importantly, simultaneous administration of an antibody blocking IL-6 inhibited the antidiabetic effects of liraglutide. Our data indicate that GLP-1 analogs suppress obesity and diabetes in part through an IL-6-dependent induction of adipocyte beiging. Disclosure A. D. Gutierrez: None. Z. Gao: None. V. Hamidi: None. M. Kolonin: None. Funding National Institutes of Health (5R21DK122234 to A.D.G.)