The role of glucocorticoids in the activation of hepatic gluconeogenesis in mice exposed to the cold

• Grant number: 24/18457-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2024
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Carlos Carvalho Navegantes
• Grantee: Gustavo Fortunato Passos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The interaction between the sympathetic nervous system (SNS) and the CRH-ACTH-Adrenal axis (also known as the HPA axis, hypothalamic-pituitary-adrenal) is a central aspect of the stress response, which, when deregulated, can compromise an individual's metabolic health. In previous studies, we demonstrated that the SNS in rodents exposed to cold activates hepatic gluconeogenesis via CREB (cAMP response element-binding protein) signaling, but nothing is known about the physiological role of glucocorticoids in this metabolic challenge. Therefore, the present study will test the hypothesis that corticosterone (glucocorticoid in rodents) participates in the activation of the hepatic gluconeogenesis gene program during thermal stress through its transcription factor FoxO1 (Forkhead Box Protein 1). For this, 12-week-old male C57/Bl6J mice will be used, both sham-operated and subjected to bilateral adrenal gland removal (ADX), or treated with mifepristone (a glucocorticoid receptor antagonist), and exposed to room temperature (28°C) and cold (4°C) for 6 hours. Another group of animals will be treated with a pharmacological FoxO1 inhibitor (iFoxO1) and subjected to the same stress. During this time, blood glucose levels and temperature will be measured, and at the end, the animals will be euthanized for plasma and liver collection for biochemical analyses (glycogen, ketone bodies, FFA, and TAG), hormonal analyses (insulin, glucagon, and corticosterone), and molecular analyses of protein content and phosphorylation status by western blot (FoxO1 and PEPCK) and gene expression by RT-PCR (G6pc, Pck1, and Foxo1). These results will be important for a better understanding of the hormonal mechanisms controlling hepatic gluconeogenesis in situations of metabolic stress.