Scientists are tracing how a lipid-signaling receptor linked to blood pressure, insulin resistance, and weight gain could open a new route for treating metabolic syndrome, but human therapies still need clinical testing.
Review: GPR75: A Newly Identified Receptor for Targeted Intervention in the Treatment of Obesity and Metabolic Syndrome. Image Credit: TarikVision / Shutterstock
In a recent review published in the journal Cardiology in Review, the authors highlight G protein-coupled receptor 75 (GPR75) as a potential therapeutic target for metabolic syndrome (MetS) and obesity.
MetS encompasses a range of conditions, including obesity, hypertension, insulin resistance, and high cholesterol. It also increases the risk of diabetes, cardiovascular disease (CVD), and stroke. Although several treatments are available, efforts are needed to identify more effective and specific drug targets. In this context, GPR75, a selective receptor for 20-hydroxyeicosatetraenoic acid (20-HETE), appears to be a promising target.
20-HETE is a bioactive lipid that plays an important role in the development of obesity and hypertension. GPR75/20-HETE binding triggers a signaling cascade responsible for various physiological functions. Their binding has been shown in experimental models to promote vascular dysfunction, remodeling, and hypertension, and is also implicated in obesity, oxidative stress, and inflammation. The present review examined GPR75/20-HETE signaling and provided perspectives on targeting GPR75 for the treatment of MetS and obesity.
The GPR75 and 20-HETE apparatus
The cytochrome P450 family 4 (CYP4) enzymes catalyze the synthesis of 20-HETE from arachidonic acid. In the vasculature, 20-HETE generation occurs mainly in vascular smooth muscle cells (VSMCs) and is limited under nonhypoxic conditions but increases in ischemic or hypoxic conditions. In endothelial cells (ECs), GPR75/20-HETE binding induces dissociation of the GTP-binding protein 11, enabling the association of GPR75 and G protein-coupled receptor kinase-interacting protein 1 (GIT1).
Subsequently, SRC proto-oncogene, non-receptor tyrosine kinase (cSRC) dissociates from GIT1 and activates epidermal growth factor receptor (EGFR). This triggers a cascade of downstream effects, resulting in elevated angiotensin-converting enzyme (ACE) expression, endothelial dysfunction, and increased cytokine production. GPR75/20-HETE binding also increases VSMC contractility, enhancing sensitization to contraction stimuli. In simple terms, this pathway links excess lipid signaling to blood-vessel dysfunction, insulin resistance, and weight gain.
In animal models of 20-HETE-dependent hypertension, GPR75 knockdown has been reported to prevent increases in blood pressure and the associated vascular remodeling and injury. This suggests that GPR75 expression is necessary for the pro-hypertensive effects of 20-HETE in these models. In addition, 20-HETE can induce adipogenesis in vitro and has been reported to be elevated in diabetic and obese subjects.
The inositol triphosphate/diacylglycerol cascade is activated upon GPR75/20-HETE binding, thereby increasing intracellular calcium levels and activating protein kinase C (PKC). Subsequently, the insulin receptor (IR) is dephosphorylated and thereby deactivated, leading to insulin resistance. Moreover, increases in 20-HETE lead to the phosphorylation of IR substrate 1 (IRS-1), inhibiting IR signal transduction and, thereby, aggravating peripheral insulin resistance.
Oxidative stress
Oxidative stress plays a critical role in the development of EC damage and insulin resistance. Increased visceral adiposity and body mass index (BMI) can upregulate adipogenesis and reduce adiponectin. This leads to inflamed adipocytes and the production of reactive oxygen species (ROS). ROS oxidize high-density lipoprotein (HDL) to oxidized HDL.
Increased levels of oxidized HDL lead to the release of cytokines, such as tumor necrosis factor (TNF)-α and interleukin-1, contributing to obesity’s pro-inflammatory state. In addition, increased oxidized HDL levels can elevate 20-HETE, triggering a cascade that increases angiotensin II and ROS. Subsequently, ROS increases inflammation and the number of large dysfunctional adipocytes, resulting in a cycle of chronic obesity, endothelial dysfunction, and CVD. The review also describes heme oxygenase-1 as an antioxidant defense pathway that may counter ROS-driven endothelial dysfunction and metabolic injury.
GPR75: a potential therapeutic target
Whole-exome sequencing of over 640,000 people identified 16 genes associated with BMI. Of these, GPR75 loss-of-function (LOF) variants showed the strongest association with decreased BMI. Predicted LOF (pLOF) or truncated variants of GPR75 were detected in four individuals per 10,000, and these people had lower body weight and BMI and a reduced risk of obesity.
In a high-fat diet (HFD) mouse model, GPR75 knockout led to a substantial reduction in weight gain. Knockout also correlated with improved insulin sensitivity and glycemic control, supporting GPR75 as a potential target for the treatment of MetS and obesity. A follow-up analysis later reported that the protective effects were due to elevated activity rather than reduced appetite.
Further, GPR75-deficient mice showed neither increased fat volume nor reduced muscle volume. This suggests that GPR75 blockers may prevent or reduce obesity through mechanisms distinct from those of current therapeutics. Overall, the authors argue that GPR75 could be a viable target for reducing weight, oxidative stress, and hypertension, and for augmenting insulin sensitivity, potentially without loss of lean mass.
Summing up
Together, the widespread impact of MetS significantly affects patients, increasing their risk of health complications and burdening health systems. Given that 20-HETE promotes obesity and hypertension, the identification of its receptor, GPR75, has unveiled opportunities for future therapeutic targeting.
The authors suggest that GPR75-targeted strategies could potentially provide durable metabolic benefits without the lean mass loss associated with some current weight-loss therapies, but this remains to be tested clinically.
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