Effects of Estrogen Receptor Alpha in the Liver on Autophagy and Insulin Resistance

• Grant number: 24/06556-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2024
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: Felipe Nunes de Camargo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Consumption of a high-fat diet largely contributes to the development of metabolic syndrome, which includes atherogenic dyslipidemia, high blood pressure, cardiovascular diseases and type 2 diabetes mellitus, with the central factor of this syndrome generally being the development of insulin resistance. associated with obesity. It is possible to observe that these metabolic complications are less prevalent in young women than in men of the same age or postmenopausal women. Several mechanisms are currently considered to cause insulin resistance, such as abnormal lipid metabolism, ectopic lipid accumulation, mitochondrial dysfunction, in addition to inflammation and endoplasmic reticulum stress. Furthermore, another complication associated with metabolic diseases is Non-Alcoholic Fatty Liver Disease. In recent decades, clinical and experimental studies have revealed that estradiol (the most potent estrogen) contributes enormously to glycemic homeostasis, probably via the alpha isoform of its receptor. In fact, reduced estrogen concentration during menopause is associated with increased visceral fat and, in turn, metabolic diseases such as insulin resistance, diabetes and cardiovascular disease. The same phenotype is observed in female rodents that undergo ovariectomy, with this phenotype reverting after hormonal treatment with estradiol. In addition to estradiol, another factor that has been demonstrated to impact metabolism is autophagy, which is a process of recycling cytoplasmic cellular content, conserved throughout evolution and present in several systems, with the main function of maintaining homeostasis, through the degradation of cellular components - such as proteins, lipids, organelles, glycogen, among others - which promotes the conservation of the "quality" of cellular content. Specifically in the liver, dysregulation of the autophagic process leads to the accumulation of hepatic triglycerides and the development of steatosis, which is generally associated with insulin resistance. As the liver is a central organ in the control of metabolic homeostasis, the general objective of this project is to study (in vivo) the function of estrogen receptor alpha (ER±) on hepatic metabolism using animals with deletion of ER± specifically in the liver (Cre-Lox system).