Role of Estrogen Receptor Alpha in White Adipose Tissue Physiology and Metabolism

• Grant number: 24/23408-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: Jorge Felipe Argenta Model
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Obesity is defined as a state in which excessive fat accumulation occurs in white adipose tissue (WAT). This is a chronic disease that affects more than 1 billion people worldwide. Several comorbidities are associated with obesity, including hyperlipidemia, insulin resistance (IR), and type 2 diabetes (T2DM). Due to its classic function as the main energy store, WAT is one of the tissues that undergoes the most changes due to obesity. Obesity, together with WAT expansion, leads to increased infiltration of immune cells, production of pro-inflammatory cytokines, and endoplasmic reticulum stress. Important aspects related to obesity and inflammation in humans are sex-dependent, with some of the most notable differences involving the distribution and function of WAT. Estradiol (E2), the main estrogen in females, plays a protective role against metabolic disorders. This hormone modulates body fat distribution, reduces inflammation, and regulates energy metabolism, largely through estrogen receptor alpha (ER¿). In women, the decline in E2 during menopause is associated with weight gain and redistribution of visceral fat, increasing the risk of metabolic diseases. In WAT, E2 promotes subcutaneous lipid deposition, associated with reduced inflammation and metabolic risk. Activation of ER¿ stimulates leptin production, thermogenesis and suppresses autophagy, while its inhibition promotes an increase in the expression of pro-inflammatory cytokines in adipocytes. In addition, the absence of ER¿ promotes an increase in WAT, adipocyte size, adipocyte number, lipoprotein dysregulation, and the development of impaired glucose tolerance and insulin resistance. In addition to its actions in WAT, E2 inhibits endoplasmic reticulum stress by acting in different tissues.This study aims to explore how E2 and ER¿ influence the morphology, inflammation, endoplasmic reticulum stress and thermogenesis of WAT, in addition to their effects on the global metabolism of females. For this purpose, female mice divided into SHAM and ovariectomized groups, fed with a standard or high-fat diet, will be used. Additionally, E2 replacement (OVX+E2) and the absence of ER¿ in adipocytes (Ad-ER¿ KO) will be evaluated to investigate the specific relevance of the receptor. (AU)