Long-term effects of MTCH2 knockdown by AAV8 of mice on a high-fat diet

• Grant number: 24/05621-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 29, 2024
• End date: August 28, 2025
• Field of knowledge: Health Sciences - Nutrition
• Principal Investigator: Leandro Pereira de Moura
• Grantee: Vivian Cristina da Cruz Rodrigues
• Supervisor: Veerle Rottiers
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Institution abroad: University of California, Berkeley (UC Berkeley), United States
• Associated to the scholarship: 20/08398-7 - Effects of MTCH2 muscle-specific gene deletion on apoptotic, lipogenic, oxidative, insulin and inflammatory pathways in the muscle of lean and obese animals submitted to short-term aerobic exercise, BP.DR

Abstract

Mitochondrial carrier homolog 2 (MTCH2) was identified as one of the genes associated with obesity in the genome-wide association study. Animals that overexpress the MTCH2 protein have a more significant accumulation of body fat, elevated mitochondrial dysfunction, and hyperglycemia. On the other hand, animals that had MTCH2 deletion in muscle tissue were protected from weight gain and hyperinsulinemia. Two-week AAV8 MTCH2 depletion in obese mice fed a high-fat diet caused a reduction of body weight. However, in a long-term high-fat diet it is unknown which tissues MTCH2 are depleted after injection of the AAV8-shMTCH2 and if the effects on weight observed previously can be recapitulated. Therefore, the present proposal will investigate the long-term effects of AAV8-induced MTCH2 depletion on mice on a high-fat diet. C57BL/6 mice will be divided into 2 groups and after 6 weeks on a high-fat diet, one group will be injected with an AAV8-shMTCH2 virus to knockdown MTCH2. Throughout the experiment, the animals' weight will be monitored. Following 6-8 weeks, the tissues such as the liver, adipose tissue, and muscle will be collected for further genetic and biomolecular analysis. The changes in lipid composition will be analyzed by metabolomics, gene expression by RNA sequencing, and mitochondrial morphology and function by histology, microscopy, immunofluorescence, and oxygen consumption. At the end of the present study, if our hypothesis is confirmed, we could better understand the contribution of MTCH2 on lipid homeostasis, and also the driving mechanisms in this process.