Insulin Receptor Regulation across Adipose Tissues and Its Impact on Systemic Metabolism

Introduction and Objective: Adipose tissue dysfunction is strongly associated with insulin resistance and type 2 diabetes (T2D). Insulin signaling plays crucial roles in maintaining adipose homeostasis. In humans, insulin receptor (INSR) expression is decreased in white adipose tissue (WAT) from aged, obese, and T2D individuals. Methods: To define the role of insulin receptor reduction in fat in whole-body physiology, we generated mice with heterozygote loss of Insr in adipocyte (IR-HET) by crossing adiponectin-Cre+/- and Insr-flox+/- mice. Results: The resultant mice exhibited ~20% to ~50% reductions in Insr in epididymal WAT (eWAT), inguinal WAT (iWAT), and brown adipose tissue (BAT). This was paralleled by a similar reduction in insulin signaling in these fats, but not in liver and muscle, as manifest by decreased phosphorylation of Insr Tyr1150/1151, Akt Ser473, and Erk Thr202/204. IR-HET mice showed significant reductions of BAT and iWAT weight, but a mild decrease of eWAT and body weight. IR-HET mice maintained normal plasma triglyceride and glucose levels but exhibited insulin resistance and hyperinsulinemia. This reduction in Insr also resulted in significant and distinct changes in gene expression across eWAT, iWAT, and BAT with 224 to 931 genes upregulated and 814 to 1205 genes downregulated. Interestingly, only 6 upregulated and 5 downregulated genes were present in all 3 fats, indicating the unique role of Insr in each depot. Differentially expressed genes in eWAT were most enriched in cilium movement, whereas in iWAT they were in the adaptive immune response and in BAT in fatty acid synthesis. Single nuclei sequencing of human WAT also showed more than 500 genes that correlated with INSR dosage. Conclusion: Thus, the reduction in adipocyte Insr in rodents and humans alters gene expression and fat function, highlighting its critical role in maintaining fat and whole-body homeostasis. Identification of these dose-dependent Insr-regulated genes provides new insights into the complex nature of insulin resistance response in different fats. Disclosure: Y. Yu: None. X. Liu: None. H. Camara: None. Y. Tseng: Consultant; Paratus Sciences. Other Relationship; Novo Nordisk, ATCC, Biohaven. Consultant; LyGenesis. C. Kahn: Consultant; Novo Nordisk, Cellarity. Advisory Panel; TIXiMED. Board Member; 1825.