PPARα induces IL-6 to trigger diabetic cardiomyopathy

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Obesity is accompanied by elevated plasma free fatty acid (FFA), which, in turn, induces insulin resistance and diabetes. More than half of diabetic patients develop myocardial dysfunction, known as diabetic cardiomyopathy, characterized by left ventricular hypertrophy, fibrosis and diastolic dysfunction. Some patients develop heart failure with preserved ejection fraction (HFpEF). Thus, elucidating the underlying molecular mechanism of diabetic cardiomyopathy is critically important. The hearts of patients with obesity, insulin resistance, type II diabetes, and HFpEF often develop a low grade of inflammation. Pro-inflammatory cytokines and chemokines, including TNF-, IL-1, IL-6, and MCP-1, produced in adipose tissues, infiltrating inflammatory cells, and local cell types, including endothelial cells and cardiomyocytes (CMs), play an essential role in mediating fibrosis, hypertrophy, diastolic dysfunction and insulin resistance, thereby contributing to the development of diabetic cardiomyopathy. However, which cell types produce cytokines during the initial phase of diabetic cardiomyopathy and what the underlying mechanism is are poorly understood. Furthermore, the significance of the local mechanisms compared to systemic inflammation remains to be clarified. Our preliminary results suggest that FFA activates IL-6 production in CMs through a PPAR-NF-B-dependent mechanism, which, in turn, promotes the development of diabetic cardiomyopathy. In this study, we will clarify the role of PPAR and IL-6 in CMs in mediating cardiac dysfunction in response to high fat diet (HFD) consumption and the molecular mechanisms through which elevated FFA stimulates IL-6 in CMs. Our overall hypotheses are: PPAR in CMs is a sensor of increased FFA that triggers diabetic cardiomyopathy through production of IL-6. Increases in plasma FFA directly stimulates IL-6 transcription in CMs through increased binding of PPAR-NF-B heterodimer to the NF-B element located in the IL-6 promoter. IL-6 produced in CMs acts as an autocrine/paracrine factor to induce diabetic cardiomyopathy. Aim 1: Elucidate the role of cardiac endogenous PPAR and IL-6 in mediating the initial development of diabetic cardiomyopathy. Aim 2: Elucidate the molecular mechanism by which PPARstimulates transcription of IL-6 in CMs. Aim 3: Evaluate whether suppression of PPAR-NF-B heterodimer formation inhibits CM production of IL-6 and the development of diabetic cardiomyopathy in response to HFD consumption. We will address these issues using newly generated CM-specific loss-of-function mouse models. In addition, we will obtain a proof-of-concept that PPAR-NF-B heterodimer is a novel therapeutic target for diabetic cardiomyopathy. We expect that our study should demonstrate a novel mechanism stimulating local innate production of IL-6 in CMs and its role in mediating the initial development of diabetic cardiomyopathy which is highly relevant to many patients with obesity and borderline metabolic syndrome.