Defining the role of succinate in obesity cardiomyopathy

• Grant number: 24/20372-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Henrique Marchesi Bozi
• Grantee: Livia Rodrigues Costa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Obesity is a major public health problem worldwide. The global prevalence of obesity has more than doubled over the past four decades, affecting more than a billion people. The prevalence of obesity for most countries has been increasing since 1980s. Beyond this, obesity has been declared a disease per se that impairs quality of life and reduces life expectancy. Notably, two-thirds of obesity-related mortality is attributable to cardiomyopathies. The molecular mechanisms behind obesity-induced cardiac dysfunction are still unknown; however, the pathophysiology of obesity cardiomyopathy involves a continuous process of molecular, metabolic and structural remodeling that leads to the impairment of heart contractility. Studies in pre-clinical models and humans found that obesity is associated with increased extracellular levels of succinate. This metabolite is an intermediate of the citric acid cycle that was thought to be predominantly intracellular. However, we and others recently found that succinate can not only be selectively secreted in the systemic milieu, but also regulates the function of distal tissues through its ligation and activation of the succinate receptor 1 (SUCNR1). In rodents, succinate administration leads to cardiomyocyte hypertrophy and impairment of calcium transient. Additionally, elevation of extracellular succinate has been linked to a higher risk of cardiomyopathy. Although these findings indicate extracellular succinate as a potential mediator of obesity cardiomyopathy, the role of succinate-SUCNR1 signaling in the heart are still unknown. Here, we will test the hypothesis that high levels of extracellular succinate driven by obesity lead to cardiomyopathy through the activation of succinate- SUCNR1 signaling. To do this, we will generate a mouse model lacking SUCNR1 (SUCNR1KO). Next, we will thoroughly characterize cardiac function, structure and molecular parameters in wild-type and SUCNR1KO mice, under baseline and high-fat diet-induced obesity conditions.