Endocrine Abstracts

JOINT1315

Metabolic syndrome is characterized by the hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to increased steroidogenesis. The molecular signaling mechanisms underlying HPA axis alterations in metabolic diseases remain poorly understood. In this study, our objective was to investigate how changes in signaling molecules within both plasma and adipose tissue contribute to the regulation of adrenal steroidogenesis in metabolic diseases and elucidate the modified response of adrenocortical and pituitary cells. Using a mouse model of obesity induced by a high-fat diet (HFD), we aimed to pinpoint the onset of changes in steroid hormone response. We investigated the adrenal glands and plasma of mice at different time points up to 16 weeks of HFD. We observed a significant increase in adrenal gland weight along with increased levels of corticosterone in mouse plasma. These changes were preceded by elevated insulin concentrations in the mouse plasma as early as 8 weeks of HFD. 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 HFD. 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 spheroid diameter along with an increase in mRNA expression of steroidogenic genes, indicating enhanced cell expansion and steroidogenesis, while adiponectin decreased the spheroid diameter, indicating an inhibitory effect on steroidogenesis. We have previously shown that insulin can enhance ACTH secretion in primary pituitary cells. To elucidate the underlying mechanism of how insulin acts in these in vitro systems, we performed bulk RNA sequencing of adrenocortical and pituitary cells with and without insulin stimulation. When comparing insulin-induced differentially expressed genes (DEGs) in both cell types, we observed upregulation of genes related to cholesterol biosynthesis and fatty acid transport. This could indicate that insulin stimulates de novo cholesterol biosynthesis, the precursor for steroid synthesis. In adrenocortical cells, insulin-induced DEGs were uniquely attributed to cholesterol transport, inner mitochondrial membrane and respiratory chain, and steroid synthesis. Hence, an overall effect of insulin on cholesterol metabolism could be crucial for regulating cholesterol transport for subsequent steroid synthesis in adrenocortical cells. Together, 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.