Stress can lead to an increase in body fat and obesity that are major clinical conditions preceding the metabolic syndrome. In a state of metabolic syndrome, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis occurs, resulting in increased steroidogenesis and alteration of cortisol secretion. This increased sensitivity of the HPA axis can lead to the development of comorbidities or severe illness in patients with metabolic diseases and vice versa. The molecular signaling mechanisms that cause such alterations in the HPA axis in metabolic diseases remain elusive. Within my PhD project we are aiming to characterize the adaptation of the HPA axis with specific focus on the adrenal gland to metabolic diseases. Previous studies indicate a role of insulin and adipokines released by the adrenal-surrounding adipose tissue into the plasma to affect the regulation of adrenal steroidogenesis. Here, we aim to study the role of these signaling molecules in regulating adrenal steroidogenesis in metabolic diseases and decipher the altered response of adrenocortical cells. Using mouse models of obesity and diabetes, we aim to identify the onset of the changes in steroid hormone response in relation to the metabolic status of the mice. To determine the direct effect of these signaling molecules on adrenocortical cells, we are using in vitro spheroid cultures generated from primary adrenocortical cells. Using different treatments of insulin and adipokines we aim to identify the cellular and molecular changes in adrenocortical cells and how they can be translated in vivo. Based on these results, we want to determine the role of insulin and the adipose tissue in regulating the adrenal gland function in metabolic diseases. The outcomes will pave the way for a better understanding of HPA axis activity during metabolic stress adaptation, and the role of the HPA axis in patients suffering from metabolic diseases. 

The HPA axis as an enhancer of metabolic syndrome. The sympatho-adrenomedullary (SAM) system results in the production of catecholamines (CAT) in the adrenal medulla (M) as indicated by violet arrows. The Renin-angiotensin-aldosterone (RAAS) system results in the production of aldosterone (ALDO) in the zona glomerulosa (zG) as indicated by blue arrows. The HPA axis stress signaling results in the production of cortisol (CORT) from the zona fasciculata (zF) as indicated by green arrows. Cortisol (CORT) can induce the accumulation of visceral fat (green arrow). Adipose tissue secretes adipokines and inflammatory cytokines that can affect hormone production in the adrenal gland (red arrows). Metabolic diseases are associated with alterations in the SAM, RAAS system, and HPA axis signaling, and can affect the cardiovascular system, insulin sensitivity, gluconeogenesis, and dyslipidemia (red lightning).