Effects of progesterone on energy metabolism and insulin resistance in menopause

Author(s)

Carlos Henrique Zanello Talarico

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-05-26

Examining board members

João Paulo Gabriel Camporez; Carla Roberta de Oliveira Carvalho; Alceu Afonso Jordao Junior

• Advisor: João Paulo Gabriel Camporez

Abstract

High-fat diet largely contributes to the development of the metabolic syndrome, which includes atherogenic dyslipidemia, high blood pressure, cardiovascular disease and type 2 diabetes mellitus, and the central factor of this syndrome is usually 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 accumulation, mitochondrial dysfunction, in addition to inflammation and endoplasmic reticulum stress. In addition, another complication associated with metabolic diseases is Non-Alcoholic Fatty Liver Disease. In recent decades, clinical and experimental studies have revealed that estradiol (the more potent estrogen) contributes enormously to glycemic homeostasis, probably via the alpha isoform of its receptor. In fact, reduced estrogen levels during menopause are 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 reversed after hormonal treatment with estradiol. However, the same consensus does not exist in women during menopause, replacement with progesterone or conjugated estradiol and progesterone, since, while some studies demonstrate the beneficial effects of combined hormone replacement during this period, other studies were unable to observe such benefits. Based on what was observed in clinical studies with menopausal women and knowing that most hormone replacement treatments are performed with the hormones estradiol and progesterone together, the objective of this work was to investigate the effects of progesterone on energy metabolism and resistance to insulin in an experimental model of menopause (ovariectomized female mice) fed a high-fat diet. The specific objectives of the work were: a) To evaluate the effect of progesterone on glucose tolerance through a glucose tolerance test; b) Analyze the accumulation of lipids in the liver and skeletal muscle; c) Analyze gene and protein expression of inflammatory markers and lipid synthesis. Our results revealed that on a high-fat diet, progesterone replacement alone does not seem to influence glucose homeostasis and/or act on ectopic lipid accumulation. The conjugated hormone replacement of estradiol and progesterone showed an indication of improvement in the glucose tolerance test, in the evaluation of the plasma insulin levels and reduction of the accumulation of ectopic lipids similar to the replacement with estradiol alone. However, progesterone has been shown to have an effect on glucose metabolism and insulin sensitivity on a standard diet, revealing that progesterone can counteract the protective effects of estradiol and lead to impaired glucose tolerance and reduced insulin sensitivity under this regimen. We believe that these results will help expand knowledge about hormone replacement in postmenopausal women associated with Metabolic Syndrome and the development of Non-Alcoholic Fatty Liver Disease. (AU)

• FAPESP's process: 20/16160-0 - Progesterone effects on energy metabolism and insulin resistance in menopause
• Grantee: Carlos Henrique Zanello Talarico
• Support Opportunities: Scholarships in Brazil - Master