Exogenous succinate stimulates brown adipose tissue thermogenesis and increases body mass reduction induced by a glp-1 analog

Author(s)

Rodrigo Stellzer Gaspar

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2023-01-27

Examining board members

Licio Augusto Velloso; Gabriel Forato Anhê; Lígia de Moraes Antunes Correa; Lucila Leico Kagohara Elias; Maria Lúcia Bonfleur

• Advisor: Licio Augusto Velloso

Abstract

Obesity is one of the leading non-communicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through an uncoupling protein-1-dependent uncoupled mitochondrial respiration, this has generated interest on its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue proteome, and how exogenous succinate could impact body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like peptide-1 receptor agonist, liraglutide. In the first part of the study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the levels of 177 brown adipose tissue proteins and enrichment analysis showed these are mostly associated with changes in both mitochondrial structure and function. In the second part of the study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of both exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone to promote body mass reduction, food energy efficiency reduction, food intake reduction and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate alone, but not liraglutide, promoted a significant increase on the blood levels of several medium- and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction. Thus, succinate emerges as a potential strategy to promote advances in the treatment of obesity (AU)

• FAPESP's process: 18/19942-0 - Central role of GLP-1 agonists (liraglutide) and antiepileptic (topiramate) in treatment of high-fat diet-induced Obesity
• Grantee: Rodrigo Stellzer Gaspar
• Support Opportunities: Scholarships in Brazil - Doctorate