GPR75 in obesity-driven cardiovascular and metabolic complications

抽象概括 肥胖和相关的代谢并发症，包括代谢综合征和糖尿病， 心血管疾病的发病率。这项提案的总体目标是确定细胞机制， G蛋白偶联受体75（GPR 75）的激活导致肥胖症导致的代谢和心血管并发症。在 在上一个资助期，我们提供了强有力的证据，证明GPR 75是20-羟基二十碳四烯酸的受体。 （20-HETE），一种血管活性和促炎脂质介质，结合并通过其触发其作用。20-HETE 与心血管和代谢疾病包括高血压的发展和进展有关， 中风、心肌梗塞、糖尿病和代谢综合征。我们最近的研究清楚地表明，20-HETE- 介导高血压和饮食驱动的代谢中的血管功能障碍（例如，胰岛素抵抗）和心血管（例如， 高血压）并发症通过其配对和激活GPR 75。脂肪组织和血管内皮 是导致肥胖症心脏代谢紊乱的关键它们都表达GPR 75，是20-HETE的主要靶点 生物作用在内皮中，20-HETE通过与GPR 75结合，解偶联eNOS，诱导ACE并激活内皮细胞。 NF-κB炎症程序。20-HETE刺激脂肪细胞肥大并干扰脂肪细胞胰岛素信号传导， 葡萄糖稳态和线粒体功能。高血压和肥胖患者的内皮功能障碍 和动物模型伴随着循环20-HETE水平的数倍增加。因此， 假设20-HETE通过其对血管内皮和脂肪组织的作用作为重要的决定因素， 肥胖导致的心血管和代谢并发症。重要的是，在约600，000的大规模外显子组测序中， 我们发现，GPR 75变异体的功能丧失与消瘦和防止肥胖有关 （Science，2021）。这一发现已在Gpr 75缺失小鼠中得到验证（Science，2021和初步结果）， 令人信服地暗示20-HETE-GPR 75配对在肥胖症及其心脏代谢并发症的发病机制中 并要求确定潜在的机制。因此，我们假设20-HETE-GPR 75配对 促进饮食驱动的心脏代谢并发症（例如，高血糖、胰岛素抵抗、高血压）， 损害内皮和脂肪细胞功能的机制。我们进一步认为，20-HETE-GPR 75配对 控制脂肪细胞和内皮细胞之间的相互作用，这有助于心血管和代谢 肥胖症的并发症这一假设将在三个特定的目标，评估内皮细胞的贡献进行测试， 和脂肪细胞特异性Gpr 75对饮食驱动的肥胖的影响，并研究内皮脂肪细胞 串扰取决于20-HETE-GPR 75配对。

Abstract Summary Obesity and the associated metabolic complications including metabolic syndrome and diabetes significantly contribute to cardiovascular morbidities. The overall goal of this proposal is aimed at identifying cellular mechanisms that link activation of the G-protein coupled receptor 75 (GPR75) to obesity-driven metabolic and cardiovascular complications. In the last funding period, we provided strong evidence that GPR75 is the receptor to which 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoactive and pro-inflammatory lipid mediator, binds and through which it triggers its actions. 20-HETE has been implicated in the development and progression of cardiovascular and metabolic diseases including hypertension, stroke, myocardial infarction, diabetes and metabolic syndrome. Our recent studies clearly demonstrated that 20-HETE- mediates vascular dysfunction in hypertension and diet-driven metabolic (e.g., insulin resistance) and cardiovascular (e.g., hypertension) complications through its pairing and activation of GPR75. The adipose tissue and the vascular endothelium are key to the ensuing cardiometabolic disorders in obesity. They both express GPR75 and are prime targets for 20-HETE bioactions. In the endothelium, 20-HETE, through its binding to GPR75, uncouples eNOS, induces ACE and activates the NF-κB inflammatory program. 20-HETE stimulates adipocyte hypertrophy and interferes with adipocyte insulin signaling, glucose homeostasis and mitochondria function. Endothelial dysfunction in hypertensive subjects and obesity in humans and animal models are accompanied by several fold increases in circulating 20-HETE levels. Accordingly, it is reasonable to assume that 20-HETE through its actions on the vascular endothelium and adipose tissue acts as a significant determinant of obesity-driven cardiovascular and metabolic complications. Importantly, in a large-scale exome sequencing of ~600,000 individuals, we revealed that loss of function GPR75 variants are associated with leanness and protection from obesity (Science, 2021). This finding, which has been validated in Gpr75 null mice (Science, 2021 and Preliminary Results), compellingly implicates the 20-HETE-GPR75 pairing in the pathogenesis of obesity and its cardiometabolic complications and calls for identification of the underlying mechanisms. Consequently, we hypothesized that 20-HETE-GPR75 pairing promotes diet-driven cardiometabolic complications (e.g., hyperglycemia, insulin resistance, hypertension) by a mechanism that impairs endothelial and adipocyte function. We further argue that 20-HETE-GPR75 pairing governs a crosstalk between adipocytes and endothelial cells which contributes to cardiovascular and metabolic complications in obesity. This hypothesis will be tested in three specific aims that assess the contribution of endothelial- and adipocyte-specific Gpr75 to diet-driven obesity and examine potential mechanisms governing endothelial-adipocyte crosstalk that are dependent on 20-HETE-GPR75 pairing.