Energy metabolism regulation by beta-type estradiol receptor in hepatocytes and adipocytes submitted to energy overload

• Grant number: 21/04781-3
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): March 01, 2022
• Effective date (End): February 29, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal researcher: Alicia Juliana Kowaltowski
• Grantee: Débora Santos Rocha
• Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Estradiol receptors (ERs) stimulation shows significant metabolic benefits after menopause. However, it is also related to an increased risk of hormone-dependent cancer and thrombosis. In this sense, the selective activation of the beta-type estradiol receptor (ER²) has shown antitumor action, besides the ability to modulate metabolic indicators of mitochondrial function. Surprisingly, to our knowledge, no studies have been conducted to elucidate the role of ER² in mitochondrial function of estrogen-deficient females previously submitted to the energy overload model. Therefore, our proposal is to evaluate the ER² role in key metabolic tissues, liver and adipose tissue, in the energy overload model. The experimental design consists of four stages. The first aims to assess whether ER² modulation in Sprague-Dawley rats attenuates the effects of a high-fat diet plus ovariectomy. The other experiments will be conducted with in vitro treatment, in lineages of hepatocytes HepG2 and adipocytes 3T3 L1 submitted to energy overload by glucose and fatty acid (glucolipotoxicity). In the second stage, the outcomes of ER² agonist in lineages will be compared to in vivo outcomes, with emphasis on cellular energy reserves evaluation. The focus of the third stage is to assess whether there is a direct mitochondrial action of ER² agonist in isolated mitochondria, or only in intact cells, with emphasis on different substrates flux to ATP replacement. Finally, the molecular mechanisms modulated by ER² agonist will be evaluated in relation to glycolysis, gluconeogenesis, oxidative phosphorylation, citric acid cycle, to lipid beta-oxidation.(AU)