SAT272 Insulin Signaling In Hyperactivation Of The HPA Axis In Metabolic Diseases

Disclosure: D. Cozma: None. P. Siatra: None. I. Oikonomakos: None. D. Kalra: None. U.A. Friedrich: None. A. Dahl: None. S.R. Bornstein: None. S. Zeissig: None. C.L. Andoniadou: None. C. Steenblock: None. Stress can lead to an increase in body fat and obesity as main clinical conditions preceding the metabolic syndrome [1]. In metabolic stress, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed, resulting in increased steroidogenesis and alteration of cortisol secretion [1]. This increased sensitivity of the HPA axis may be related to the development of comorbidities or severe illness in patients with metabolic diseases and vice versa. Disorders of the HPA axis, e.g., Cushing’s disease, resulting from overproduction of ACTH, share similar clinical symptoms with metabolic diseases [1]. The molecular signaling mechanisms that cause such changes in the HPA axis under metabolic stress remain elusive. Previous studies indicate a role of insulin in the regulation of adrenal steroidogenesis by upregulating the transcriptional activity of NR5A1 [2]. Here, we study the molecular mechanisms to insulin-induced hyperactivation of the HPA axis and characterize the molecular changes that lead to altered cortisol secretion. We generated non-adherent spheroids from primary adrenocortical cells in vitro and treated these with insulin. This resulted in an increase of spheroid diameter over time [Slope: 5.163 ± 0.994; P=0.0139; n=11], compared to control [Slope: -4.058 ± 0.987; P=0.0261; n=10], indicating greater cell expansion following insulin treatment. Similarly, repeating this experiment with adherent primary anterior pituitary stem cell colonies showed an increase in colony size when treated with insulin compared to control [Diameter: 1221.0 ± 290.9 µm vs. 914.5 ± 256.2 µm; P=0.0079; n=3]. This indicates that the stem cell populations of the adrenal and pituitary gland are responsive to insulin stimulation, likely leading to increased proliferation. This is complementary to our previous studies where we revealed increased secretion of aldosterone in insulin-stimulated adrenocortical cultures [3]. To identify signaling pathways related to insulin stimulation, we performed bulk RNA sequencing of in vitro primary cultures of adrenocortical and pituitary cells with and without insulin treatment. Analysis of these data sets reveals specific signaling pathways that are candidates in regulation of metabolic stress in vivo. Using mouse models of obesity and diabetes along with genetic lineage-tracing studies, we aim to decipher the role of these pathways on HPA axis stem/progenitor cells during metabolic stress. The outcomes will pave the way for a better understanding of HPA axis activity during metabolic stress adaption, and the role of the HPA axis in patients suffering from metabolic diseases. References: [1] Pasquali et al. Ann N Y Acad Sci. 2006. [2] Kinyua et al. Sci Rep. 2018. [3] Werdermann et al. Mol Metab. 2021. Presentation: Saturday, June 17, 2023