1094-OR: Redistribution of Insulin Resistance Uncouples Obesity from Hepatic Steatosis under Flattened Glucocorticoid Rhythms

Introduction and Objective: Flattened glucocorticoid (GC) rhythms are a hallmark of chronic stress and a driver of obesity. However, it remains unclear whether the metabolic profile of GC-flattened obesity mirrors the dysfunction of caloric excess. We determined if disrupted GC timing generates a distinct metabolic phenotype from diet-induced obesity (DIO). Methods: We compared mice with flattened GC rhythms (via corticosterone pellets) to High-Fat Diet (HFD) controls. Metabolic flux was assessed using hyperinsulinemic-euglycemic clamps with tissue-specific glucose uptake. Signaling was evaluated via immunoblotting and gene expression in liver, adipose, and muscle. Results: Despite a standard chow diet and no increased food intake, GC flattening induced profound obesity (>2.5-fold increase in fat mass by Day 21), comparable to HFD feeding. Strikingly, this obesity was accompanied by increased glucose tolerance despite severe global insulin resistance, and was uncoupled from hepatic steatosis. GC-flattened mice maintained normal circulating lipid and glucose levels and normal insulin-mediated suppression of endogenous glucose production. Adipose tissue maintained preserved insulin-mediated suppression of lipolysis, thus keeping circulating non-esterified fatty acids low. Insulin resistance was concentrated in skeletal muscle, with ~70% reduction in insulin-stimulated glucose uptake and selective fast-twitch fiber atrophy. Rather than globally impairing insulin action as in HFD feeding, disrupted GC timing redistributes insulin resistance to skeletal muscle while preserving hepatic and adipose insulin responsiveness, thereby maintaining whole-body glucose and lipid homeostasis despite obesity and severe muscle insulin resistance. Conclusion: Flattened GC rhythms induce a metabolically compensated obesity distinct from caloric excess. This tissue-specific reorganization uncouples adiposity from hepatic steatosis and identifies GC rhythmicity as a key regulator of cross-tissue insulin action. Disclosure M.N. Teruel: None. A. Agas: None. S. Sharma: None. L.P. Saavedra: None. J. Lungstrum: None. J.W. Jayakumari: None. A. Arzeno: None. Funding American Diabetes Association (1-26-PDF-1121), NIH NIDDK (R01DK131432)