GPR75: A Newly Identified Receptor for Targeted Intervention in the Treatment of Obesity and Metabolic Syndrome

Abstract

Metabolic syndrome increases the risk of stroke, cardiovascular disease, and diabetes. The morbidity and mortality associated with this constellation of risk factors are equally alarming when considering the economic and global significance that this epidemic has on an institutional and patient level. Despite several current treatments available, there needs to be a continuous effort to explore more specific and effective druggable entities for preventative and therapeutic interventions. Within this context, the G-protein coupled receptor, GPR75, is an attractive pharmacological target. GPR75 and its association with its ligand, 20-hydroxyeicosatetraenoic acid, have been shown to promote hypertension, inflammation, obesity, and insulin resistance. This review will help shed light on this novel signaling pathway and offer a perspective on a promising new direction of targeting different aspects of the metabolic syndrome involving GPR75. Gene targeting of GPR75 is more effective than current pharmacologic therapies without the known side effects.

FIGURE 1.

Obesity induces dysfunctional adipose tissue creating a chronic inflammatory state – a hallmark of the metabolic syndrome. Increased BMI and obesity increase adipogenesis and production of adipocytokines, resulting in decreased adiponectin. This generates further ROS resulting in dysfunctional adipocytes causing insulin resistance, hypertension, and hyperlipidemia. BMI indicates body mass index; ROS, reactive oxygen species.

FIGURE 2.

A, The expression of CYP4 enzymes is upregulated by environmental factors such as HFD, at the molecular level by androgen receptors and microRNAs, and by hormones such as angiotensin II, endothelin, and norepinephrine. B, 20-HETE binds to GPR75 and triggers a cascade of downstream effects such as vascular ACE expression of the RAAS pathway, endothelial dysfunction/inflammation, increased contractility, and subsequent vascular remodeling, hypertension, and cardiovascular disease. C, 20-HETE-GPR75 binding induces eNOS uncoupling from its chaperone protein HSP90, causing decreased nitric oxide availability and increased ROS, resulting in impaired relaxation of vessels and creation of prohypertensive and profibrotic signals (cytokine production), leading to further endothelial dysfunction. D, c-SRC disassociates with GIT1 and activates EGFR via phosphorylation. MAPK is then activated, and NFkB is translocated into the nucleus, leading to increased ACE transcription, further eNOS uncoupling, cytokine production, and vasoconstriction. E, GPR75-GIT1 association frees protein kinase C and c-SRC, which both phosphorylate MaxiKB and, in turn, inhibit BKca channels, resulting in calcium efflux and depolarization, leading to vasoconstriction. 20-HETE-GPR75 binding increases Rho-kinase activity and phosphorylation of myosin light chain, enhancing sensitization to contraction stimuli such as Ang II, norepinephrine, phenylephrine, and endothelin. 20-HEDE indicates 20-hydroxyeicosatetraenoic acid; ACE, angiotensin-converting enzyme; c-SRC, SRC proto-oncogene, non-receptor tyrosine kinase; EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; GIT1, G-protein-coupled receptor-kinase interacting protein-1; HFD, high-fat diet; MAPK, mitogen-activated protein kinase; RAAS, renin-angiotensin-aldosterone system.

FIGURE 3.

A, 20-HETE binds to GPR75 and stimulates the IP₃/DAG cascade, leading to increased intracellular Ca²⁺ and activation of PKC. B, Phosphatases are activated, leading to dephosphorylation of the insulin receptor, and its deactivation leads to insulin resistance. Increases in 20-HETE phosphorylate the adaptor protein IRS-1 and contribute to inhibiting the insulin receptor signal transduction and enhancing peripheral insulin resistance. C, Increased BMI and visceral adiposity (via high-fat diet and obesity) upregulate adipogenesis and cytokines, and decrease adiponectin, promoting insulin resistance. This leads to inflamed adipocytes and increased production of ROS. D, Increased ROS oxidizes HDL (Ox-HDL). E, This releases cytokines IL-1 and TNFα, causing further dysfunction and inflammation of adipose tissue. All this contributes to the proinflammatory state of obesity. F, Ox-HDL increases 20-HETE levels. G, Increased 20-HETE-GPR75 binding results in NF-kB translocation to the nucleus, RAAS activation, increased angiotensin II, and increased production of ROS. H, This cascade further exerts influence by increasing large dysfunctional adipocytes and inflammation and creating a cycle of chronic obesity, cardiovascular disease, and EC dysfunction. The activation of RAAS is a crucial link between obesity, insulin resistance, hypertension, and cardiovascular disease, ultimately contributing to metabolic syndrome. 20-HEDE indicates 20-hydroxyeicosatetraenoic acid; BMI, body mass index; EC, endothelial cell; HDL, high-density lipoprotein; NF-kB, nuclear factor kappa B; PKC, protein kinase C; RAS, renin-angiotensin-system; ROS, reactive oxygen species.