HPA-Axis Suppression Drives Durable Metabolic Improvements In Murine Multiple Models Of Metabolic Disease Via Central And Peripheral Mechanisms I

Chronic exposure to excess glucocorticoid levels results in broad metabolic derangements, while suppression of glucocorticoid levels leads to improvements in multiple aspects of metabolic health despite remaining difficult to target pharmacologically. Here, we utilize a monoclonal antibody against CRF, the parent activator of the HPA-Axis, to achieve durable suppression of plasma glucocorticoid levels without inducing adrenal failure.

In multiple mouse models of metabolic disease and obesity, including in diet-induced obese animals treated for up to 8 consecutive months, long-term treatment with this antibody resulted in significant reductions in weight trajectory, significantly improved body composition, and broad improvement in metabolic parameters. Parallel assessments were performed in lean animals. Using multi-tissue transcriptomic and proteomic assessments, we identified glucocorticoid responsive genes that were strongly correlated with metabolic efficacy and drug treatment.