Scientists are tracking how lipid-signaling receptors linked to blood pressure, insulin resistance, and weight gain may open up new avenues for treating metabolic syndrome, but human treatments still require clinical trials.
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 a magazine Cardiology reviewThe authors highlight G protein-coupled receptor 75 (GPR75) as a potential therapeutic target for metabolic syndrome (MetS) and obesity.
MetS includes a variety of conditions such as obesity, hypertension, insulin resistance, and high cholesterol. It also increases your risk of diabetes, cardiovascular disease (CVD), and stroke. Several treatments are available, but 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 signaling cascades responsible for various physiological functions. Their binding has been shown in experimental models to promote vascular dysfunction, remodeling, and hypertension, and is also thought to be involved in obesity, oxidative stress, and inflammation. In this review, we have discussed GPR75/20-HETE signaling and provided a perspective on targeting GPR75 for the treatment of MetS and obesity.
GPR75 and 20-HETE equipment
Cytochrome P450 family 4 (CYP4) enzymes catalyze the synthesis of 20-HETE from arachidonic acid. In the vasculature, 20-HETE production occurs primarily in vascular smooth muscle cells (VSMCs) and is limited in non-hypoxic conditions but increases in ischemic or hypoxic conditions. In endothelial cells (ECs), binding of GPR75/20-HETE induces dissociation of GTP-binding protein 11, allowing binding of GPR75 to G protein-coupled receptor kinase-interacting protein 1 (GIT1).
Subsequently, the SRC proto-oncogene, non-receptor tyrosine kinase (cSRC), dissociates from GIT1 and activates the epidermal growth factor receptor (EGFR). This triggers a cascade of downstream effects, leading to increased angiotensin-converting enzyme (ACE) expression, endothelial dysfunction, and increased cytokine production. GPR75/20-HETE binding also increases VSMC contractility and increases sensitization to contractile stimuli. Briefly, this pathway links excessive lipid signaling to vascular dysfunction, insulin resistance, and weight gain.
In animal models of 20-HETE-dependent hypertension, knockdown of GPR75 has been reported to prevent increases in blood pressure and associated vascular remodeling and injury. This suggests that GPR75 expression is required for the prohypertensive effect of 20-HETE in these models. Furthermore, 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 by GPR75/20-HETE binding, which increases intracellular calcium levels and activates protein kinase C (PKC). The insulin receptor (IR) is then dephosphorylated and inactivated, causing insulin resistance. Furthermore, increased 20-HETE causes phosphorylation of IR substrate 1 (IRS-1), inhibiting IR signaling, thereby worsening peripheral insulin resistance.
oxidative stress
Oxidative stress plays an important role in EC damage and the development of insulin resistance. Increased visceral fat percentage and body mass index (BMI) can upregulate adipogenesis and decrease adiponectin. This causes fat cells to become inflamed and produce reactive oxygen species (ROS). ROS oxidizes high-density lipoprotein (HDL) to oxidized HDL.
Increased oxidized HDL levels cause the release of cytokines such as tumor necrosis factor (TNF)-α and interleukin-1, contributing to the pro-inflammatory state of obesity. Additionally, increased oxidized HDL levels may increase 20-HETE, triggering a cascade that increases angiotensin II and ROS. ROS then increase inflammation and increase the number of large dysfunctional adipocytes, leading to a cycle of chronic obesity, endothelial dysfunction, and CVD. In this review, heme oxygenase-1 is described as an antioxidant defense pathway that may counter endothelial dysfunction and metabolic injury caused by ROS.
GPR75: a potential therapeutic target
Whole exome sequencing of more than 640,000 people identified 16 genes associated with BMI. Of these, GPR75 loss-of-function (LOF) variants showed the strongest association with lower BMI. Predictive LOF (pLOF) or truncating variants of GPR75 were detected in 4 per 10,000 people, 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 significantly reduced 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 subsequent follow-up analysis reported that the protective effect was due to increased activity rather than decreased appetite.
Furthermore, GPR75-deficient mice showed neither increased fat mass nor decreased muscle mass. This suggests that GPR75 blockers may prevent or reduce obesity through mechanisms different from current treatments. Overall, the authors argue that GPR75 could be a viable target to reduce body weight, oxidative stress, hypertension, and enhance insulin sensitivity without losing lean body mass.
summary
At the same time, the widespread effects of MetS have a significant impact on patients, increasing the risk of complications and burdening healthcare systems. Given that 20-HETE promotes obesity and hypertension, the identification of its receptor GPR75 reveals a potential future therapeutic target.
The authors suggest that strategies targeting GPR75 may provide durable metabolic benefits without the loss of lean body mass associated with some current weight loss therapies, but this needs to be tested clinically.
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