GPR75 in obesity-driven cardiovascular and metabolic complications

GPR75 在肥胖引起的心血管和代谢并发症中的作用

• 批准号: 10633523
• 负责人: Michal Laniado Schwartzman
• 金额: $ 56.72万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633523
• 关键词: Adipocytes; Adipose tissue; Amino Acids; Androgens; Animal Model; Attenuated; Binding; Biology; C-terminal; COVID-19; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cells; Chromosomes; Classification; Coculture Techniques; Communicable Diseases; Couples; Cytochrome P450; Data; Development; Diabetes Mellitus; Diet; Endothelial Cells; Endothelium; Epidemic; Functional disorder; Funding; G-Protein-Coupled Receptors; GPR75 gene; Genes; Goals; High Fat Diet; Human; Hydroxyeicosatetraenoic Acids; Hyperglycemia; Hyperinsulinism; Hypertension; Hypertrophy; Immunologics; Impairment; Individual; Inflammatory; Insulin Receptor; Insulin Resistance; Knockout Mice; Ligands; Link; Liver; Liver diseases; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Mixed Function Oxygenases; Monitor; Morbidity - disease rate; Mus; Muscle Contraction; Myocardial Infarction; Nonesterified Fatty Acids; Obesity; Orphan; Pathogenesis; Phenotype; Phosphorylation; Plasma; Play; Production; Proteins; Relaxation; Risk Factors; Role; Science; Signal Transduction; Skeletal Muscle; Smooth Muscle; Stroke; Systemic Therapy; Tail; Testing; Thinness; Tissues; Transgenic Mice; Variant; Vascular Diseases; Vascular Endothelium; Visceral fat; Weight Gain; Wild Type Mouse; antagonist; blood glucose regulation; cardiometabolism; driving force; endothelial dysfunction; exome sequencing; experimental study; feeding; global health; human model; hypertensive; insulin receptor substrate 1 protein; insulin signaling; lipid mediator; loss of function; novel; novel therapeutics; obesity development; overexpression; prevent; programs; receptor

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.

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，显着贡献 心血管病。该提案的总体目标旨在确定连接的细胞机制 G蛋白耦合受体75（GPR75）激活肥胖驱动的代谢和心血管并发症。在 在最后一个资金期间，我们提供了有力的证据，表明GPR75是20-羟基二乙烯酸酯的接收器 （20-HETE）是一种血管活性和促炎性脂质介体，结合并通过其触发其作用。 20-hete 在心血管和代谢性疾病（包括高血压）的发展和进展中已隐含 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代谢（例如胰岛素抵抗）和心血管（例如，例如， 高血压）并发症通过其配对和激活GPR75。脂肪组织和血管内皮 是确保肥胖症中心脏代谢疾病的关键。他们都表达GPR75，并且是20-Hete的主要目标 生物行为。在内皮中，通过与GPR75结合的20-HETE，Uncouples Enos诱导ACE并激活 NF-κB炎症计划。 20-Hete刺激脂肪细胞肥大和干扰脂肪细胞胰岛素信号传导， 葡萄糖稳态和线粒体功能。高血压受试者和人类肥胖症的内皮功能障碍 动物模型伴随着循环20-HETE水平的数量增加。根据这是合理的 假设通过其在血管内皮和脂肪组织上的作用20-Hete充当重要的确定剂 肥胖驱动的心血管和代谢并发症重要的是，在大规模的外显子组测序中约为600,000 个人，我们透露功能丧失GPR75变体与瘦身和免受肥胖症的保护有关 （科学，2021年）。这一发现已在GPR75无效小鼠中得到验证（科学，2021年和初步结果）， 迫切地在肥胖症的发病机理及其心脏代谢并发症中实现20-HETE-GPR75配对 并要求识别基本机制。因此，我们假设20-Hete-GPR75配对 通过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。我们进一步争辩说20-Hete-GPR75配对 控制脂肪细胞和内皮细胞之间的ACROSTALK，这有助于心血管和代谢 肥胖的并发症。该假设将以三个特定目的进行检验，以评估内皮的贡献 和脂肪细胞特异性的GPR75至饮食驱动的对象并检查有关内皮脂肪细胞的潜在机制 取决于20-HeTe-GPR75配对的串扰。