1556-P: Glucocorticoid-Induced Insulin Secretion via the Hypothalamic–Pituitary–Adrenal–Islet Axis Is Needed for Proper Body Weight Regulation and Pancreas Development

Prohormone convertase 1/3 (PC1/3) is a protease involved in processing of various prohormones. Inactivation mutations in PC1/3 are associated with severe obesity in mice and humans. Mechanistically, it is not well understood which misprocessed hormones induce this obesity phenotype. PC1/3 processes proopiomelanocortin (POMC) into peptides that regulate body weight via modulating the melanocortin system. To shed light on this mechanism, we deleted PC1/3 from POMC-expressing tissues, thereby blocking the processing of POMC to melanocortin-stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH). Surprisingly, body weight was only mildly and transiently increased in young POMC-specific PC1/3 knockout mice, however later in life a prominent underweight developed. These mice had an impaired hypothalamic-pituitary-adrenal (HPA) axis which resulted in inadequately low basal and ACTH-stimulated circulating glucocorticoid levels. Further, basal circulating insulin levels were strongly reduced and glucose tolerance impaired. In aged underweight PC1/3 knockout mice, corticosterone replacement therapy increased body weight to the level of control mice and normalized insulin levels as well as glucose tolerance. In addition, glucose-stimulated insulin secretion from isolated islets and total islet insulin content from POMC-specific PC1/3 knockout mice were reduced. In line with this, pancreas weight and beta-cell mass were reduced, suggesting that there are islet intrinsic developmental and secretory pathologies present in these mice. Our data show that insufficient levels of endogenous glucocorticoids negatively impact pancreas development and insulin secretion, and that this is associated with an impaired body weight development. All these phenotypes are reversible by steroid replacement therapy, suggesting that the HPA axis regulates body weight development via insulin secretion.