Loss of GPR19 drives obesity-related cardiac dysfunction in mice

Abstract

Background: Obesity is the second leading cause of preventable death in the United States and serves as a fundamental risk factor for cardiovascular disease. Dysregulated energy metabolism in hearts from obese subjects constrains cardiac contractile function under conditions of increased workload. G protein-coupled receptor (GPCR) signaling cascades play a key role in cardiovascular homeostasis, and are potential therapeutic targets to alleviate obesity-induced cardiac dysfunction. GPR19 is a poorly characterized class A orphan GPCR that is differentially expressed in several peripheral tissues, including robust expression in the heart. Recent reports from our group implicate GPR19 in a novel signaling pathway regulating mitochondrial energy metabolism in cardiac cells. However, evidence of its pathophysiological relevance in systemic or tissue-specific homeostasis has yet to be elucidated. Hypothesis: We hypothesize that GPR19 signaling mediates nutrient signaling and cardiac energy metabolism to preserve myocardial contractile function in diet-induced obesity. Methods: We used novel whole-body GPR19 knockout mice and subjected them to metabolic cage, echocardiography, and isolated perfused working heart analysis. This preliminary characterization was designed to understand the systemic effects of GPR19 depletion on cardiac and whole-body physiology under low-fat and high-fat fed conditions. Results: We report that GPR19 KO mice exhibit sex-dependent changes in both body and heart weight, increased energy expenditure, decreased physical activity, and markers of altered cardiac hemodynamics and energy metabolism. Conclusion: These findings define a new role for the GPR19 signaling pathway in the regulation of cardiac metabolic homeostasis, and thus highlight it as a potential target for therapeutic interventions in obesity-induced cardiovascular dysfunction. The project described was supported by NIGMS T32GM133332 and NHLBI R01HL147861. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.