Charcaterization of the mechanisms underlying the changes in energy balance and metabolism induced by fenofibrate

• Grant number: 23/05190-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2023
• End date: May 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Isabela Sandroni Quaresma da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM

Abstract

White adipose tissue major roles are to store excess of energy from diet as triacylglycerol and secrete hormones. Brown adipose tissue, on the other hand, expresses the uncopling protein 1 (UCP1) that when properly activated uncouples proton gradient at inner mitochondrial membrane releasing energy as heat. Fenofibrate is a ligand for the peroxisome proliferator activated receptor alpha (PPARa) clinically used to reduce hypertriglyceridemia, that when administred to mice reduces body weight and adiposity and increase UCP1 content in brown adipose tissue. In the liver, fenofibrate promotes the simultaneous activation of de novo fatty acid synthesis and beta oxidation creating a futile metabolic cycle that may increase energy expenditure. Whether fenofibrate promotes this futile metabolic cycle in adipose tissue is unknown. Based on these findings, we will test herein the hypothesis that the reduction of body weight and adiposity induced by fenofibrate dependes on the activation of UCP1 and the futile metabolic cycle in liver and adipose tissue. To test this hypothesis, wild type and UCP1 deficient mice fed with a balanced diet rich in carbohydrates or a high fat diet will be treated or not with fenofibrate (30 mg/kg/dia) during 8 weeks at 30°C and evaluated for body weight, food intake, energy efficiency, thermogenic capacity, body temperature, masses of adipose tissue, liver and skeletal muscle masses, glucose and insulin tolerance (GTT and ITT), serum levels of glucose, triacylglycerol and cholesterol, liver and adipose tissue histology, whole body oxygen consumption and mitochondrial respiration in brown adipose tissue, de novo lipogenesis and beta-oxidation in liver and adipose tissue. In a second protocol, fenofibrate will be administrated along a inhibitor of the enzyme fatty acid synthase and mice will be evaluated form the same parameters.