3057-LB: GLP-1 Receptor Agonist Treatment Promotes IL6-Dependent Activation of Brown Adipogenesis Program and Glucose Uptake in Adipose Tissue of Insulin-Resistant Humans

Introduction and Objective: Adipocyte browning, inducible in adipose tissue (AT), confers metabolic protection via increased glucose uptake and uncoupled thermogenesis. IL6 signaling mediates GLP1 receptor agonist (GLP1RA)-induced AT browning in mice. Whether this translates to human metabolism remains unknown. Here, we investigated the role of IL6 in human AT after GLP1RA therapy. Methods: Data were analyzed from a placebo-controlled, crossover clinical trial in 18 insulin-resistant adults without diabetes. Subjects received dulaglutide or placebo (vitamin B12) for 6 weeks, followed by 3-week washout, followed by the opposite drug/placebo for 6 weeks. Post-intervention assessments included PET-CT measuring the uptake of glucose analog 18F-FDG, plasma analysis, and AT analysis by qRT-PCR. To evaluate the impact of AT on IL6 expression levels, treatment arms were stratified into statistically distinguishable high- vs low-IL6 mRNA subgroups. Results: Following dulaglutide therapy, the high-IL6 mRNA subgroup (n=9, 4M / 5F, median age 38 years, BMI 31.1 kg/m2, HbA1C 5.6%) was compared to the low-IL6 mRNA subgroup (n=8, 2M / 6F, median age 41 years, BMI 28.9 kg/m2, HbA1C 5.5%). High-IL6 AT exhibited significantly elevated expression of browning markers Prdm16 (p < 0.01), UCP1 (p < 0.05), and Tert (p < 0.01), compared to low-IL6 AT. 18F-FDG uptake increased significantly (p < 0.05) compared to low-IL6 AT. These parameters positively correlated with AT IL6 expression. AT analysis for UCP1 expression confirmed the presence of brown adipocytes. Following placebo, no statistically significant differences were seen in the aforementioned outcomes between both subgroups. No statistically significant differences were seen between both subgroups for body weight, plasma GLP1, IL6, free fatty acids, glucose, or insulin in either dulaglutide or placebo arms. Conclusion: We conclude that GLP1RA promote AT metabolic activation, which is dependent on IL6 expression induction in AT.