DEFINING THE ROLE OF SUCCINATE IN THE CARDIOPROTECTIVE EFFECT OF BROWN ADIPOSE TISSUE

• Grant number: 24/19201-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2025
• End date: May 31, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Henrique Marchesi Bozi
• Grantee: Larissa Brito Vieira de Melo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/07724-9 - Defining the role of succinate signaling in the heart, AP.JP

Abstract

Brown adipose tissue is specialized in heat production. This biological phenomenon, known as thermogenesis, happens in futile energy-consuming cycles that uncouple metabolic oxidation from ATP production. For instance, the expression of the uncoupling protein 1 (UCP1) allows the proton gradient generated during oxidative phosphorylation to dissipate through the mitochondrial inner membrane without ATP production. This not only increases energy expenditure, but also promotes systemic benefits, including a reduction in cardiovascular risk. Indeed, brown adipose tissue loss-of-function leads to cardiovascular abnormalities, such as hypertension, cardiac hypertrophy, and fibrosis. Although the molecular mechanisms behind the cardioprotective effect of brown adipose tissue are still poorly understood, there is a strong rationale for identifying such mechanism as a means toward exploiting their therapeutic potential. Recent studies have shown that UCP1-expressing brown adipocytes can uptake and oxidate succinate from extracellular media. Succinate is a metabolic intermediate of the citric acid cycle that can regulate tissue physiology through the ligation to and activation of the succinate receptor 1 (SUCNR1). Indeed, chronic elevation of extracellular succinate has been shown to increase the risk of cardiovascular diseases and impair cardiomyocyte function. These findings not only suggest that maintaining low extracellular levels of succinate is critical for cardiac function, but also indicate that brown adipose tissue-mediated succinate uptake and oxidation is cardioprotective. To test this hypothesis, we will thoroughly characterize cardiac physiology, structure and molecular parameters in transgenic mouse models lacking UCP1 and SUCNR1, under baseline and high-fat diet-induced cardiac dysfunction conditions.