Involvement of adipocyte peroxisomes in the development of obesity and metabolic actions of the PPAR³ agonist pioglitazone in mice

• Grant number: 24/12973-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Érika Vicência Monteiro Pessoa
• 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

There are three types of adipocytes, the white one, which has low mitochondrial density, reduced oxidative capacity and stores energy in the form of lipids; brown, which has high mitochondrial and peroxisomal density and oxidizes fatty acids, glucose and amino acids to produce heat; and beige, which, depending on the current stimulus, can behave as a white adipocyte (high-fat diet) or brown (adrenergic activation). Peroxisomes play an important role in long chain fatty acid oxidation and biosynthesis of plasmalogens, lipid mediators, docosahexaenoic acid (DHA) and reactive oxygen species, but their involvement in the development of obesity and insulin resistance is unknown. Interestingly, drugs that increase peroxisomal biogenesis in adipocytes such as ligands for peroxisome proliferation activating receptors gamma (PPAR³) increase adipocyte oxidative capacity, promote beige adipocyte recruitment, improve insulin sensitivity and glucose and lipid homeostasis and reduce tissue inflammation. Despite enhanced biogenesis in adipocytes, the involvement of peroxissomes in the metabolic actions of the PPAR³ ligand pioglitazone are unknown. Therefore, in this proposal, we will investigate the involvement of adipocyte peroxisomes in the development of diet-induced obesity and insulin resistance, as well as, as mediators of the metabolic actions of the PPAR³ ligand pioglitazone. For this, mice with peroxissomal deficiency (Pex5 deletion) in adipocytes and littermate controls fed with either a chow or high fat diet will be treated or not with pioglitazone (30 mg/kg/day) during 8 weeks and evaluated for body weight, food intake, energy expenditure, glucose and insulin tolerances, adipose tissue mass, lipid and glucose metabolism, respiration, thermogenesis and inflammation.