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Effect of increased estrogen receptor alpha expression by adeno-associated virus on hepatic metabolism

Grant number: 19/18965-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2022
Field of knowledge:Biological Sciences - Physiology
Principal researcher:João Paulo Gabriel Camporez
Grantee:Felipe Nunes de Camargo
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/04956-5 - Impact of the estrogen receptor alpha on Non-Alcoholic Fatty Liver Disease and energetic metabolism of the liver, AP.JP

Abstract

Lifestyle and increased consumption of high fat diets contribute greatly to the development of obesity, insulin resistance, type 2 diabetes (DM2), and cardiovascular diseases. In addition, cardiovascular diseases associated with metabolic complications, such as insulin resistance and obesity, are less prevalent in young women than in men of the same age or postmenopausal women. Several mechanisms are essential as causes of insulin resistance, such as abnormal lipid metabolism and its ectopic accumulation, mitochondrial dysfunction, inflammation, and endoplasmic reticulum stress. One of the consequences of the Western lifestyle and high fat diet is Non Alcoholic Fatty Liver Disease (NAFLD), which affects about 30% of adults and up to 10% of children in developed countries. In the last decades, data from clinical and experimental studies have revealed that estradiol (more potent estrogen) contributes greatly to glycemic homeostasis. In fact, a reduction in the concentration of estrogen during a menopause is associated with increased visceral fat and, in turn, metabolic diseases like insulin resistance, DM2, and cardiovascular diseases. Since the liver is a central organ in the development of DM2, the general aim of this project is to study (in vivo and in vitro) estrogen receptor alpha (ER±) on liver energetic metabolism using primary cellular culture of hepatocytes and animals with modulation of ER± expression in the liver (knockdown or overexpression) through the use of Adeno-Associated Virus (AAV) for evaluation. This project allows the establishment of a new line of research in the department involving the impact of the signaling of sex hormones, such as estradiol, on energy metabolism, in addition to the mechanisms involved in the development of NAFLD and possible targets and new approaches to the treatment/prevention of NAFLD and DM2. In addition, this project allows the establishment of a "gold standard" technique of hyperinsulinemic-normoglycemic clamp in mice with the use of radioactive tracers to determine possible alterations on glucose metabolism in vivo. The establishment of this technique in the department will contribute with excellence to the high demand for phenotyping of mice regarding glucose metabolism.

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