Abstract 13903: Adipocyte PGC1-α and NOV/CCN3: Novel Targets in the Management of Obesity-Linked Cardiomyopathy

Abstract

Introduction: Chronic Obesity is frequently associated cardiac remodeling and the development of myocardial dysfunction. Oxidative stress and mitochondrial dysfunction are major factors in the development of obesity-related cardiomyopathy. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha &ltPGC-1α &gt is key in maintaining energy homeostasis and promotes reprogram white adipose into beige adipose tissue. We have reported a downregulation in epicardial PGC-1α levels in human and mice are associated with a reduction in cardiac function while increases in nephroblastoma overexpressed NOV/CCN3 is associated with severe inflammation and oxidative stress in multiple tissues. Hypothesis: Concomitant activation of PGC-1α and inhibition of NOV in the epicardial fat promotes adipocyte browning and alleviates obesity-related cardiomyopathy. Methods: Effect of PGC-1α over expression and NOV inhibition &ltshNOV&gt in transgenic mic selectively in adipose tissue on the heart in mice fed a high-fat diet &ltHFD&gt Mice were randomly divided into 4 groups &ltn= 5 -6> 1; lean &ltnormal diet&gt, 2; HFD , 3; transgenic mice on HFD + shNOV or 4; PGC-1α . Blood pressure, cardiac and adipose fibrosis and oxygen consumption , metabolic and mitochondrial markers were studied. Results: Mice fed a HFD developed decreased mitochondrial respiration. Inhibiting NOV expression in adipose tissue of obese mice in transgenic mice resulted in an increased heart mitochondria biogenesis &ltPGC-1α&gt, HO-1 and activation of mitophagy and autophagy &ltLC3B and PINK1&gt. Transgenic PGC-1α mice exhibited increased mitochondria biogenesis, integrity and beige adipocyte markers &ltPRDM16, FGF21&gt, insulin receptor phosphorylation and reduced inflammation. Conclusion: Inhibiting NOV or overexpression of PGC-1α in the epicardial fat improve the quality of adipose tissue with a positive impact on the heart by inducing mitophagy and improving mitochondrial function. Tissue-targeted manipulation of the NOV and/or PGC-1α signaling to reprogram white fat into brown fat may constitute a novel therapeutic strategy in the treatment of obesity-related cardiomyopathy.