PPARα induces IL-6 to trigger diabetic cardiomyopathy

肥胖伴随着血浆游离脂肪酸(FFA)的升高，这反过来又会导致胰岛素抵抗和 糖尿病。超过一半的糖尿病患者发展为心肌功能障碍，称为糖尿病 心肌病，以左室肥厚、纤维化和舒张期功能障碍为特征。一些病人 出现心力衰竭并保留射血分数(HFpEF)。因此，阐明潜在的分子 糖尿病心肌病的发病机制至关重要。肥胖患者的心脏，胰岛素 抵抗、II型糖尿病和HFpEF通常发展为低度炎症。促炎细胞因子 和趋化因子，包括肿瘤坏死因子-，白介素1，白介素6和单核细胞趋化蛋白-1，在脂肪组织中产生，渗透 炎症细胞和局部细胞类型，包括内皮细胞和心肌细胞(CMS)，起着重要的作用 在调节纤维化、肥厚、舒张期功能障碍和胰岛素抵抗中的作用，从而促进 糖尿病心肌病的发展。然而，在初始阶段，哪些细胞类型会产生细胞因子 糖尿病心肌病的发病机制和发病机制尚不清楚。此外， 与全身性炎症相比，局部机制的意义仍有待阐明。我们的 初步结果表明，游离脂肪酸通过依赖于-NF-B的PPAR激活CMS产生IL-6 这一机制，反过来又促进了糖尿病心肌病的发展。在这项研究中，我们将澄清 PPAR和IL-6在高脂饮食致心功能不全中的作用 消耗和FFA升高刺激CMS中IL-6的分子机制我们的整体 假设是：CMS中的PPAR是FFA增加的感应器，通过 IL-6的产生。血浆FFA水平升高通过增加血浆FFA水平直接刺激CMS患者IL-6转录 PPAR-NF-B异源二聚体与位于IL-6启动子上的NF-B元件的结合IL-6生产于 CMS作为一种自分泌/旁分泌因子诱导糖尿病心肌病。目标1：阐明 心脏内源性PPAR、和IL-6在糖尿病心肌病发病机制中的作用目标2： 阐明PPAR刺激细胞质雄性不育系IL-6转录的分子机制。目标3：评估 抑制PPAR-NF-B异二聚体的形成是否会抑制CM产生IL-6和 糖尿病心肌病的发生与高脂饲料的摄入有关。我们将通过以下方式解决这些问题 新生成的CM特有的功能丧失小鼠模型。此外，我们还将获得概念验证， PPAR-NF-B异源二聚体是治疗糖尿病心肌病的新靶点。我们希望我们的研究 应展示一种刺激CMS局部固有产生IL-6的新机制及其在 介导糖尿病心肌病的初始发展，这与许多患者高度相关 肥胖和临界代谢综合征。

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.