GPR75 in obesity-driven cardiovascular and metabolic complications

摘要摘要 肥胖和相关的代谢并发症，包括代谢综合征和糖尿病，是重要的原因 心血管疾病。这项提案的总体目标是确定将 G蛋白偶联受体75(GPR75)的激活对肥胖引起的代谢和心血管并发症的影响。在……里面 在上一个资助期，我们提供了强有力的证据，证明GPR75是20-羟基二十碳四烯酸的受体 (20-HETE)是一种血管活性和促炎脂质介质，它结合并通过它触发其行动。20-HETE 与包括高血压在内的心血管和代谢性疾病的发展和进展有关， 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- 在高血压和饮食驱动的代谢(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GPR75。脂肪组织与血管内皮细胞 是导致肥胖患者心脏代谢紊乱的关键因素。它们都表达GPR75，是20-HETE的主要目标 生物行为。在内皮细胞中，20-HETE通过与GPR75结合，解偶联eNOS，诱导血管紧张素转换酶，激活血管紧张素转换酶。 核因子-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转导， 葡萄糖动态平衡和线粒体功能。高血压患者的内皮功能障碍与人类的肥胖 而动物模型伴随着循环中20-HETE水平的几倍增加。因此，这是合理的 假设20-HETE通过对血管内皮细胞和脂肪组织的作用作为一个重要的决定因素 肥胖引发的心血管和代谢并发症的风险。重要的是，在一个约600,000的大规模外显子组测序中 我们发现，功能丧失的GPR75变异与肥胖和肥胖的保护有关 (《科学》，2021)。这一发现已经在Gpr75缺失小鼠身上得到了验证(《科学》，2021年和初步结果)， 20-HETE-GPR75配对与肥胖及其心脏代谢并发症的发病机制密切相关 并呼吁确定潜在的机制。因此，我们假设20-HETE-GPR75配对 促进饮食引起的心脏代谢并发症(如高血糖、胰岛素抵抗、高血压) 损伤内皮细胞和脂肪细胞功能的机制。我们进一步认为20-HETE-GPR75配对 管理脂肪细胞和内皮细胞之间的串扰，这对心血管和新陈代谢有贡献 肥胖的并发症。这一假说将在评估内皮细胞的贡献的三个具体目标中得到检验- 和脂肪细胞特异的Gpr75与饮食驱动的肥胖和检测调节内皮-脂肪细胞的潜在机制 串扰取决于20-HETE-GPR75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.