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）显着影响 该提案的总体目标是确定与心血管疾病相关的细胞机制。 激活 G 蛋白偶联受体 75 (GPR75) 来预防肥胖引起的代谢和心血管并发症。 在上一个资助期，我们提供了强有力的证据表明 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性脂质介质，可结合并通过其触发其作用。 与心血管和代谢疾病（包括高血压）的发生和进展有关， 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（例如胰岛素抵抗）和心血管（例如， GPR75 的配对和激活导致高血压）并发症。 它们都表达 GPR75，并且是 20-HETE 的主要靶标。 在内皮细胞中，20-HETE 通过与 GPR75 结合，解偶联 eNOS，诱导 ACE 并激活 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， 高血压受试者和人类肥胖症的葡萄糖稳态和线粒体功能。 动物模型中循环 20-HETE 水平增加数倍，因此这是合理的。 假设 20-HETE 通过其对血管内皮和脂肪组织的作用作为一个重要的决定因素 重要的是，在约 600,000 个大规模外显子组测序中。 在个体中，我们发现功能丧失的 GPR75 变体与瘦身和预防肥胖有关 （《科学》，2021 年）这一发现已在 Gpr75 缺失小鼠中得到验证（《科学》，2021 年和初步结果）， 必然涉及 20-HETE-GPR75 配对与肥胖及其心脏代谢并发症的发病机制 并要求识别潜在机制，我们追求 20-HETE-GPR75 配对。 通过以下方式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） 我们进一步认为 20-HETE-GPR75 配对是损害内皮细胞和脂肪细胞功能的机制。 控制脂肪细胞和内皮细胞之间的串扰，这有助于心血管和代谢 该假设将在三个具体目标中进行测试，以评估内皮细胞的贡献。 和脂肪细胞特异性 Gpr75 对饮食驱动的肥胖的影响，并检查控制内皮脂肪细胞的潜在机制 串扰取决于 20-HETE-GPR75 配对。