The role of GLP-1 in cardiac recovery after bariatric surgery in obesity-induced heart failure

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Project Summary Obesity cardiomyopathy is an increasingly prevalent and morbid disease of myocyte dysfunction causing heart failure due to severe obesity. Even though weight reduction through dieting fails to improve cardiac function, obesity treatment with bariatric surgery, like a sleeve gastrectomy (SG), significantly improves cardiac function. The inciting mechanisms for cardiac recovery after SG are poorly understood. This project will explore the novel hypothesis that cardiac glucagon-like peptide-1 receptor (GLP-1R) signaling results in the activation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARα), resulting in improved cardiac function. The applicant has found that a SG performed in obese rats significantly improved cardiac function, independent of weight loss, associated with increased serum GLP-1, increased cardiac PPARα, and decreased cardiac apoptosis, fibrosis and changes in substrate utilization. The specific aims of this proposal will test the hypothesis that cardiac GLP-1R stimulation activates PPARα resulting in decreased metabolic stress-induced apoptosis, fibrosis and increased β-oxidation and is the mechanism for cardiac recovery after SG. This award will produce a detailed understanding of cardiovascular pathophysiology, myocyte intracellular signaling pathways, biochemistry, and cardiac function analysis needed by the applicant. Further, this proposal allows for a rigorous training program to acquire the skills necessary to become a successful independent investigator with the mentorship of Dr. Corbett and the advisory committee. The primary goal of this mentored career development award is to determine the mechanisms for improved cardiac function after bariatric surgery and produce the preliminary studies needed to achieve extramural support via investigator initiated R01 funding by the NIH. The long-term scientific objective is to understand the mechanisms of interaction between bariatric surgery, obesity, and heart failure and translate these findings into surgical and non-surgical metabolic interventions. The Medical College of Wisconsin (MCW) provides an excellent environment for translational cardiovascular research. MCW's Cardiovascular Center and Clinical and Translational Science Institute provide excellent core resources and a strong collaborative environment to successfully perform the proposed studies and develop strong independent lines of investigation.