2432-P: Distinct Regulation of Insulin Action in Different Adipose Depots Contributes to Their Differential Roles in Insulin Resistance and Metabolic Syndrome

Introduction and Objective: Different adipose tissue (AT) depots are differentially associated with insulin resistance, type 2 diabetes, and metabolic syndrome, with positive effects of brown AT (BAT) and negative effects of visceral AT (VAT), while subcutaneous AT (SAT) is physiologically neutral. Methods: To understand these differences, we performed hyperinsulinemic-euglycemic clamps in 3-month-old male mice and assessed insulin action in each depot by RNA sequencing. Results: This revealed depot-specific transcriptional responses to insulin, with ~1100 insulin up-/down-regulated genes in BAT, 1197 insulin-regulated genes in SAT, and 2096 insulin-regulated genes in VAT. Among these, only 124 genes were commonly upregulated and 138 downregulated by insulin across all 3 depots. The former were enriched in genes involved lipid biosynthesis and metabolic processes, while the commonly down-regulated genes were related to protein ubiquitination. These commonly regulated genes were associated with increases in transcription factors (TFs) of the Bhlhe40, Bhlhe41 and Srebf1. Importantly, 50-53% genes in BAT and SAT, and over 68% of genes in VAT, were regulated by insulin in a depot specific manner. These included genes involved in cell cycle, DNA repair, apoptosis, as well as some secreted proteins and genes involved in fatty acid metabolism. These differences were associated with major differences in TFs regulated by insulin in different depots, with Zic1 selectively upregulated by insulin in BAT, while Ncoa2 or Stat3 was selectively reduced in SAT or VAT, respectively. These are in addition to adipose depot-specific transcriptional responses to insulin controlled by the FoxOs. Conclusion: Thus, individual depots show complex gene expression responses to insulin stimulation in vivo, including differences in major transcription factors driving the response. These differences are fundamental to the impact of these different depots on metabolic health and the pathogenesis of diabetes. Disclosure Y. Yu: None. X. Liu: None. J.K. Kim: None. C. Kahn: Consultant; Current; TIXiMED, Alnylam Pharmaceuticals, Inc. Board Member; Current; 1825 Therapeutics. Consultant; Ended; Cellarity.