Endocrine Abstracts

Metabolic syndrome is characterized by the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased steroidogenesis and altered cortisol secretion. The molecular signaling mechanisms underlying HPA axis alterations in metabolic diseases remain poorly understood. In this study, our objective is to investigate how changes in signaling molecules within both plasma and adipose tissue contribute to the regulation of adrenal steroidogenesis in metabolic diseases and to elucidate the modified response of adrenocortical cells. Using a mouse model of obesity induced by a high-fat diet, we aim to pinpoint the onset of changes in steroid hormone response, correlating these changes with the metabolic status of the mice. We observed increased leptin and insulin concentrations in the mouse plasma as early as 8 weeks of high-fat diet feeding. Further, our findings revealed increased expression of Lep (leptin), and decreased expression of Adipoq (adiponectin) in the adipose tissue surrounding the adrenal upon 16 weeks of high-fat diet. These changes coincided with a rise in adrenal gland weight and elevated levels of steroid hormones, suggesting that increased steroidogenesis could directly be caused by interactions between adipokines and adrenocortical cells. To explore the direct impact on adrenocortical cells, we treated primary adrenocortical cell-derived spheroids with insulin and adiponectin. We observed that insulin induced an increase in diameter, indicating enhanced cell expansion and steroidogenesis, while adiponectin decreased the spheroid diameter, indicating an inhibitory effect on steroidogenesis. Bulk RNA sequencing of these in vitro primary spheroid cultures with and without insulin stimulation revealed differential expression of steroidogenic genes. Gene Set Enrichment Analysis indicated upregulation of gene sets associated with steroid biosynthesis among the top 5, suggesting a direct induction of adrenal steroidogenesis by insulin. Hyperinsulinemia together with a decreased expression of Adipoq in the peri-adrenal adipose tissue could be a cause of increased steroidogenesis observed in metabolic diseases in vivo. Our results underscore the crucial role of insulin and adipose tissue in regulating adrenal gland function in metabolic diseases contributing to a comprehensive understanding of HPA axis activity in these conditions.