2532-P: Chronic Glucocorticoid Excess Induces Hypometabolism in Gastrocnemius

Introduction and Objective: Cushing’s syndrome is defined by metabolic disruption, manifesting as increased adiposity. decreased lean mass, and higher cardiovascular risk. Despite well-described clinical manifestations, the molecular and organ-specific mechanisms driving impaired energy metabolism remain a key knowledge gap. Our objective was to identify the key metabolic tissue and the underlying molecular mechanism that drives hypometabolism in Cushing’s syndrome. Methods: We utilized a well-established rodent model of Cushing’s syndrome. We compared mice treated with 100 mcg/ml of corticosterone in their drinking water (CORT) versus mice with vehicle solution in drinking water (VEH) over 4 weeks. Young-adult male C57BL/6 mice were housed at thermoneutrality to assess basal metabolism. This model recapitulated Cushing’ syndrome including increased adiposity and loss of lean mass. We compared the bioenergetics of CORT and VEH using high resolution respirometry as well as fluorescence measurements of ATP production rate. Results: CORT significantly shifted body composition, inducing a 3-fold increase in fat mass and a 30% reduction in muscle mass.​​ This phenotype was independent of food intake. Oxygen consumption rate (OCR) only decreased in gastrocnemius (gastroc), and there was no OCR change in brown adipose tissue, inguinal white adipose tissue, kidney, liver, soleus, and tibialis anterior. In the gastroc only, there was a significant decrease in OCR per tissue and per mitochondria mass, indicating that the hypometabolic phenotype does not depend on mitochondrial biogenesis. CORT specifically decreased complex I-driven respiration in gastroc. The decrease in complex I activity did not alter the ATP production rate to OCR ratio. Conclusion: We identified that chronic glucocorticoid excess induces hypometabolism in gastroc through a decrease in mitochondrial complex I activity. The hypometabolism in gastrocnemius linked with the metabolic phenotype of Cushing’s syndrome, suggesting a potential driver of the disease. Disclosure A. Sanghi: None. S. Kajimura: Advisory Panel; Current; MoonWalk Inc. Research Support; Current; Eli Lilly and Company. Consultant; Current; Gordian Bioscience.