GPR75 in obesity-driven cardiovascular and metabolic complications

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.