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.

The metabolic syndrome comprises a spectrum of conditions that include hypertension, obesity, high cholesterol, and insulin resistance (Fig. 1). The National Health and Nutrition Examination Survey results released in 2018 show that 4 out of 10 adults were classified as obese, with an increased risk of diabetes, hypertension, hypercholesterolemia, cardiovascular disease, stroke, and cancer.¹ The National Institute of Diabetes and Digestive and Kidney Diseases Data shows that 9.2% of adults have morbid obesity, with a body mass index (BMI) of more than 40; women are affected more than men and people of color affected the most, making this a diversity and health equity issue.^2,3 There has been a dramatic rise in cardiometabolic diseases such as diabetes, hypertension, and heart disease that parallel the increases in obesity.^4,5

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.

CURRENT APPROACHES TO WEIGHT LOSS

Glucagon-like peptide-1 (GLP-1) is an incretin, a metabolically active hormone whose function is to decrease blood glucose; it is released after eating and promotes insulin release.⁶ Patients with type 2 diabetes maintain the regulatory function of GLP-1 and as a result, GLP-1 receptor agonists (GLP-1RA) have been very useful in the management of type 2 diabetes.⁷ The long-acting GLP-1RA’s such as semaglutide, liraglutide, and dulaglutide, taken weekly as subcutaneous injection, slow intestinal transit time and decrease hunger.⁸ They have gained national attention for their role in weight loss and are very popular medications for off-label use for obesity, even given the gastrointestinal side effects.⁹ Recent data show that this weight loss includes lean body mass loss, including muscle (up to 10%), which is a concern.^10–12 Patients taking these drugs have been encouraged to exercise along with the drug to avoid this concern. There is still a need for a weight loss drug that does not cause lean body muscle mass loss.

RECENT DISCOVERIES

20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid derived from the ω-hydroxylation of arachidonic acid by cytochrome P450 enzymes of the CYP4 family and plays a significant role in the development of hypertension and obesity.¹³ 20-HETE stimulates smooth muscle contractility in the vasculature, induces endothelial dysfunction, and exacerbates vascular inflammation. 20-HETE impairs insulin signaling, leading to insulin resistance and diet dependence.¹⁴

G-protein coupled receptors (GPCRs) are membrane receptors that serve as intermediaries of a myriad of physiological responses to hormones, neurotransmitters, and environmental stimuli.^14,15 GPR75, previously labeled as an orphan GPCR, has been proven to be a selective receptor for 20-HETE, which interacts with high affinity.^15,16 GPR75 is expressed in the vascular endothelium, liver, eye, kidney, lung, brain, and adipose tissue, among others, and its activation is instrumental in the signaling mechanisms that lead to and mediate the effects of the metabolic syndrome.^14,15 The binding of 20-HETE and GPR75 results in a signaling cascade responsible for the culmination of various physiologic functions (Fig. 2). It is a potential crossroad in which therapeutic targeting could halt the progression of the effects of long-standing hypertension and obesity, thus serving as a preventative target for myocardial infarction, stroke, vascular disease, and the various pathological implications of metabolic syndrome.¹⁴ The 20-HETE/GPR75 apparatus in hypertension, as seen in Figure 2, can be summarized by inducing vascular angiotensin-converting enzyme (ACE) expression of the renin-angiotensin system pathway, endothelial dysfunction and inflammation, increased contractility, and subsequent vascular remodeling and hypertension.^15,17

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.

The binding of 20-HETE to GPR75 impacts the vasculature and hypertension but is also implicated in obesity and obesity-driven hypertension. Numerous studies showed a direct relationship between BMI and 20-HETE levels in obese subjects that parallel findings in animal models of obesity, in which levels of 20-HETE in tissues and biological fluids are highly elevated,^14,15 and 20-HETE-GPR75 pairing is also linked to increased inflammation and oxidative stress. Reactive oxygen species (ROS) generated in visceral adipose tissue led to decreased adiponectin levels and inflammation of large adipocytes, further contributing to insulin resistance. High BMI and visceral adiposity are important risk factors that contribute to the upregulation of adipogenesis, increased levels of oxidized high-density lipoprotein (Ox-HDL), inflammatory cytokines interleukin (IL)-6, tumor necrosis factor alpha (TNFα), and decreased adiponectin.¹⁸ A key factor is the ability of Ox-HDL to increase 20-HETE levels, thus setting off a cascade that culminates in endothelial cell (EC) death.¹⁸

20-HETE AND GPR75 APPARATUS

The CYP4 family catalyzes the production of 20-HETE from arachidonic acid, specifically CYP4A11 and CYP4F21 isoforms in human tissues.¹⁹ As seen in Figure 2A, expression of CYP4 enzymes is regulated by transcriptional activators and the androgen receptor and subject to posttranslational regulation by microRNAs. Significantly, transcription and translation of CYPs are moderated by diet and environmental factors, such as a high-fat diet (HFD) (Fig. 2A). 20-HETE is also stimulated by angiotensin II (Ang II), endothelin, and norepinephrine (Fig. 2A). 20-HETE generation is synthesized in the microvasculature primarily by vascular smooth muscle cells (VSMC), although the vascular endothelium, especially the pulmonary endothelium, also has the capacity to produce 20-HETE.^20,21 It is not produced under homeostasis but in hypoxic/ischemic conditions^14,22 (Fig. 2A). There is also increasing evidence demonstrating 20-HETE’s importance in angiogenesis. Chen et al²³ have shown, in vitro and in vivo, that 20-HETE levels are increased under ischemic conditions despite the observation that EC in culture and vascular EC in circulatory beds have little to no 20-HETE synthase activity under nonhypoxic conditions.

In EC, the binding of 20-HETE with GPR75 triggers dissociation of the GTP-binding protein 11 (Gαq/11), allowing for GPCR-kinase interacting protein-1 (GIT1)-GPR75 association (Fig. 2B). c-SRC (SRC proto-oncogene, non-receptor tyrosine kinase) dissociates from GIT1 and transactivates epidermal growth factor receptor via phosphorylation. This leads to downstream activation of mitogen-activated protein kinase (MAPK) with a cascade resulting in nuclear factor kappa B (NF-kB) translocation into the nucleus and increased ACE expression, decreased NO availability/endothelial dysfunction, and elevated cytokine production²⁴ (Fig. 2B–E). GPR75-dependent activation of Gαq/11 also leads to activation of phospholipase C and generation of inositol triphosphate (IP₃), leading to vasoconstriction.^25,26 Subsequent GPR75-GIT1 association results in protein kinase C (PKCα) dissociation from GIT1. PKCα and c-SRC phosphorylate MaxiKB (subunit of the Ca²⁺-activated K⁺ or BKca channels). This inhibition of BKca leads to an elevation in cytosolic Ca²⁺, with subsequent influx through voltage-gated L-type Ca²⁺ channels and transient receptor potential cation channel 6 (TRPC6), a nonvoltage-gated Ca²⁺-permeable nonselective cation channel. This depolarization leads to vasoconstriction^14,15,27 (Fig. 2E). 20-HETE/GPR75 binding further elevates VSMC contractility by increasing Rho-kinase activity and the phosphorylated state of the myosin light chain, subsequently enhancing sensitization to contraction stimuli such as Ang II, norepinephrine, phenylephrine, and endothelin^28,29 (Fig. 2E).

The key to determining 20-HETE’s ability to be regulated was figuring out the crossroad in its pathway where it became functionally active. Essentially, what did 20-HETE bind to, how did that matching enable downstream effects, and could inhibiting its receptor reduce the cumulative aftermath? Garcia et al¹⁵ were able to show that in EC, 20-HETE binds and activates a receptor that elicits the epidermal growth factor receptor-MAPK-inhibitor of nuclear factor-κB kinase-NF-kB cascade, inducing ACE transcription, endothelial nitric oxide synthase uncoupling, and stimulation of cytokine production (Fig. 2C,D). In smooth muscle cells, 20-HETE-induced BKca channel inhibition mediates vasoconstriction (Fig. 2E). An additional aspect of the 20-HETE/GPR75 apparatus is its contribution to vascular modeling via increases in ROS and promotion of VSMC migration and proliferation.^14,30 Importantly, knockdown of GPR75 in animal models of 20-HETE-dependent hypertension prevented the rise in blood pressure and the associated vascular remodeling and injury.^14,15 Taken together, these findings suggested that expression of GPR75 was required for 20-HETE’s prohypertensive effects.¹⁵

20-HETE has been shown to induce adipogenesis in vitro and to increase in obese and diabetic subjects and experimental models.^14,15,17 Several studies showed a causal relationship between 20-HETE and the development of hyperglycemia and insulin resistance in mice fed a HFD.^31–33 We now understand the direct relationship between activation of GPR75 and 20-HETE and its impact on decreased insulin signaling. As seen in experimental mouse models and cultured cells, after 20-HETE binds to GPR75, the inositol triphosphate/diacylglycerol cascade is activated. This increases intracellular Ca²⁺ levels, subsequently contributing to the activation of PKC¹⁵ (Fig. 3A). Phosphatase activity is increased, and the insulin receptor (IR) is dephosphorylated, with subsequent deactivation. Deactivated IR leads to insulin resistance (Fig. 3B). Additionally, the adaptor protein, IRS-1, is phosphorylated by increases in 20-HETE. This inhibits IR signal transduction, leading to an exacerbation of peripheral insulin resistance.^31,32 High levels of 20-HETE, which lead to GPR75 activation, are positively correlated with obesity and metabolic syndrome in human and animal models, mainly by promoting a cycle of insulin resistance.³³

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.

OXIDATIVE STRESS

Oxidative stress is a critical factor in developing insulin resistance and EC damage. Increased BMI and visceral adiposity can upregulate adipogenesis, Ox-HDL, and cytokines (IL-6, TNFα), and decrease adiponectin levels (Fig. 3C). ROS are generated in inflamed adipocytes, which oxidize HDL to become Ox-HDL²⁵ (Fig. 3D). Elevated levels of Ox-HDL release IL-1 and TNFα, causing further dysfunction and inflammation of adipose tissue, all contributing to the proinflammatory state of obesity (Fig. 3E). Increased Ox-HDL has been shown to increase 20-HETE levels³⁴ (Fig. 3F). Additionally, Ox-HDL is incapable of preventing the oxidation of LDL.³⁴ This sets off a cascade resulting in NF-kB translocation to the nucleus, increased Ang II via renin-angiotensin-aldosterone system activation, and increased production of ROS³⁵ (Fig. 3G). ROS then increases the number of large dysfunctional adipocytes and inflammation, leading to a vicious cycle of chronic obesity, cardiovascular disease, and EC dysfunction^18,36 (Fig. 3H).

ANTIOXIDANT DEFENSE

Heme oxygenase 1 (HO-1) is the first line of defense against oxidant attack and is the enzyme responsible for turning free prooxidant heme into carbon monoxide (CO)/iron/bilirubin. HO-1 plays a vital role in the 20-HETE/GPR75 pathway.³⁷ Bilirubin and CO scavenge ROS and reduce oxidant stress by inhibiting nicotinamide adenine dinucleotide phosphate oxidase.^18,36 HO-1 also preserves NO, thus having a cumulative effect of preserving EC dysfunction. This results in decreased EC dysfunction that results from ROS-mediated destruction of endothelial nitric oxide synthase. HO-1 decreases NF-kB activation, attenuating Ang II-mediated superoxide production and the downhill cascade resulting in hypertension.³⁸ With insulin-resistant metabolic syndrome and obesity-generated proinflammatory adipocytes, there is increased nicotinamide adenine dinucleotide phosphate oxidase activity and ROS production.³⁹ This results in mitochondrial dysfunction, downregulation of HO-1, increased ROS, and increased Ox-HDL, a potent activator of 20-HETE, overwhelming the antioxidant activity of HO-1.^39,40

Ox-HDL potentiates adipogenesis and has been shown to activate both Ang II and 20-HETE in obese women, creating metabolic syndrome.³⁶ The result is adipose tissue inflammation, which releases adipocytokines, reduces adiponectin and Ang II secretion, and exacerbates EC dysfunction, insulin resistance, and hypertension.^18,25 The EC dysfunction is manifested by an increased level of circulating ECs in obese women.⁴¹ This creates the cascade of more EC dysfunction, atherosclerosis, and cardiorenal syndrome; HDL is essential for reverse cholesterol transport for proper cardiac physiology, and Ox-HDL interferes with reverse cholesterol transport.⁴² This results in a downregulation of heme oxygenase and an upregulation of lipid metabolism; conversely, upregulation of HO-1 reverses EC dysfunction, reduces hypertension, reverses cardiac remodeling, reduces insulin resistance, and improves metabolic syndrome.^43,44

They also compared the pharmacologic upregulation of HO-1 with an HO-1 inducer to gene transfer therapy, both improving EC dysfunction and reducing adipogenesis. Still, gene transfer therapy had a much longer-term effect on HO-1 expression by directly targeting ECs, proving viral transfection led to a more sustained effect on HO-1 and adipogenesis.⁴⁵ HO-1 has always been a reliable marker of cellular oxidative stress⁴⁶ and when it is low, the result is adipose tissue inflammation, which releases adipocytokines and reduces adiponectin and secretion of Ang II, exacerbating EC dysfunction, insulin resistance, and hypertension.^18,25

EXPERIMENTAL EVIDENCE OF THE RECEPTOR GPR75

GPR75 is the receptor responsible for 20-HETE-dependent hypertensive cascade-induced ACE expression. ACE inhibitors and Ang II receptor blockers target the renin-angiotensin-aldosterone system to normalize blood pressure. However, these drugs do not prevent 20-HETE-dependent changes in arterial media thickness, media lumen, and cross-sectional area. Only in studies involving a 20-HETE antagonist and the knockdown of the 20-HETE/GPR75 apparatus, have blood pressure and vascular remodeling been shown to be affected.^15,47 It is key to understand that 20-HETE-dependent vascular remodeling can occur even under conditions of normal blood pressure.³⁰

CYP4a12 is the primary 20-HETE-producing CYP in mice. Using CYP4a12 transgenic mice, Garcia et al¹⁵ provided conclusive evidence for the role of GPR75 in 20-HETE’s prohypertensive actions and its vascular dysfunction and remodeling effects. Mice were treated with doxycycline (DOX), a well-known upregulator of the CYP4a12–20-HETE synthase. They were separated into control (non-GPR75-targeted shRNA lentiviral particles) and treatment groups (GPR75-targeted shRNA). As expected, the control group had an acute and persistent increase in systolic blood pressure that was not observed in the GPR75 shRNA-targeted treatment group. Notably, the DOX-treated CYP4a12tg mice that received GPR75-targeted shRNA also showed the anticipated changes in microvascular remodeling, ACE expression, and sensitivity to constrictor (phenylephrine) and vasodilatory (acetylcholine) stimuli.^15,17,47 In the treatment group, GPR75 was reduced by 80% in renal preglomerular microvessels, 45% in the liver, and 80% in the heart.¹⁵

Gilani et al³¹ showed the effect of 20-HETE on HFD-induced weight gain in CYP4a12tg mice. Those animals fed an HFD showed marked weight gain compared to the control diet (CD) group, which was treated with or without DOX over 15 weeks. However, DOX-treated CYP4a12tg mice fed an HFD exhibited a significant increase in body weight compared to DOX-treated CYP4a12tg mice fed a CD. This was further evaluated in DOX-treated CYP4a12tg mice fed an HFD and additionally treated with 2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyeicosa-6(Z), 15(Z)-dienoate (20-SOLA), a known 20-HETE antagonist. This cohort of mice showed a significant reduction in weight gain compared to the lack of weight loss in 20-SOLA treated CYP4a12tg mice fed an HFD and without DOX treatment.^31,33 These findings indicate that 20-HETE strongly influences weight gain when under an HFD regimen.^31,40 In their 15-week study, Gilani et al also showed that CYP4a12tg mice on HFD or CD, or CD + DOX, did not undergo any changes in fasting blood glucose.³¹ However, the one group that increased their glucose levels was that of DOX-treated mice fed an HFD; when 20-SOLA was administered, the DOX-HFD group did not have persistent hyperglycemia.

Additionally, this same cohort had plasma insulin levels 5 times higher than those in the HFD alone cohort. The HFD cohort showed no significant difference in plasma insulin levels, like the CD or CD + DOX groups. The same pattern remained evident when comparing glucose tolerance levels at the end of the 15-week study, with the DOX + HFD cohort being the only group to show impaired glucose tolerance, with significant improvement after 20-SOLA administration. 20-SOLA did not affect blood glucose levels in the HFD cohort alone. This further suggests the necessity of CYP4a12tg induction and subsequent elevated 20-HETE to trigger insulin resistance development in response to HFD.³³ It is also important to note that 20-HETE and CYP4a12 levels were significantly increased in the plasma and visceral fat of the DOX + HFD cohort. Although all groups treated with DOX showed elevated levels, this result further displays the synergistic combined effect of HFD and elevated 20-HETE levels.³¹

The third key finding from Gilani et al³¹ was the observation of how 20-HETE impairs insulin signaling. Phosphorylation of the IR is key for its activity. In DOX-HFD mice, there was a significant reduction in phosphorylation of the IR at Tyr-972 in skeletal muscle (40%), adipose tissue (70%), and liver (60%).⁴⁸ Not surprisingly, the addition of 20-SOLA reversed phosphorylation levels. On the other hand, phosphorylation of IRS-1, an adaptor protein that signals downstream pathways, inactivates the IR. In CYP4a12tg mice, the DOX-HFD cohort exhibited a significant increase in phosphorylation of IRS-1 and a decrease in IRS-1 levels. 20-SOLA administration to this group reversed these results.³¹ This suggests that 20-HETE and its binding to GPR75 are key in developing obesity-driven insulin resistance, especially with the combined effects of elevated 20-HETE and HFD. This identifies GPR75 as a critical pharmacologic target for preventing and/or reducing high blood pressure, endothelial dysfunction, and vascular remodeling.^15,49

Despite the notable evidence supporting a pathophysiological role of 20-HETE in various aspects of metabolic syndrome, significant effort has been put into the pharmacological targeting of 20-HETE synthesis and/or actions. The inhibitors that prevent 20-HETE synthesis do so by targeting CYP. Among these, the most selective 20-HETE synthesis inhibitor is N-methylsulfonyl-12, 12-dibromododecane-11-enamide, which selectively targets CYP4A11.^31,50 20-HETE blockers, or antagonists, include the first-generation nonwater-soluble compounds 20-HEDE and N-[20-hydroxyeicosa-6(Z ),15(Z )-dienoyl]glycine.^32,51 The second-generation water-soluble compounds N-disodium succinate-20-hydroxyeicosa-6-(Z), 15(Z)-diencarboxamide, and 20-SOLA have been developed to block 20-HETE binding both in vitro and in vivo.¹⁴

Current efforts have shifted to targeting 20-HETE-GPR75 pairing. GPR75 exhibits high expression in the brain but is also found in most human tissues throughout the body. As a result of paramount studies by Garcia et al,¹⁵ Froogh et al,¹⁴ and Gilani et al,³¹ utilizing knockout mouse models of GPR75, evidence was obtained strongly suggesting an association of GPR75 with 20-HETE-dependent increase in ACE expression, hypertension, endothelial dysfunction, vascular constriction, and remodeling, hyperglycemia, HFD-dependent weight gain, and insulin resistance,^10,16 revealing GPR75 as an ideal candidate for pharmacological intervention in the treatment and prevention of the metabolic syndrome.⁵²

GPR75 GENETICS TO THERAPEUTICS

GPR75 was first identified by Tarttelin et al in 1999 and characterized as a 540 amino acid protein with 2 exons located on human chromosome 2p16⁵³. The first exon was determined to be an untranslated sequence, with the second exon being the entire translated region.⁵² Akbari et al identified 16 genes whose burden was statistically significantly associated with BMI. The only gene whose loss of function variants were most strongly associated with reduced BMI was GPR75.⁵⁴ Truncated variants or predicted loss of function (pLOF) GPR75 variants were found in ~4/10,000 people sequenced. These individuals had lower BMI, reduced body weight, and lower risk of developing obesity.⁵⁴

In a HFD model, heterozygous knockout mice were associated with a 25% reduction in weight gain, whereas the homozygous knockout cohort showed a 44% reduction. This also exhibited a positive correlation with improved glycemic control and insulin sensitivity. This further supports GPR75 as a potential therapeutic target in obesity and metabolic syndrome, in addition to exome sequencing becoming a significant aspect of identifying those at risk and further drug targets.⁵⁴ In a follow-up study, Hossain et al⁵⁵ provided evidence that the protective effect of GPR75 deficiency from obesity in mice fed HFD is associated with increased activity rather than decreased appetite. Mice with deleted GPR75 were protected against HFD-driven adiposity, adipocyte hypertrophy, and insulin resistance, possibly attributed to reduced inflammation, protected mitochondrial function, and preserved insulin signaling. In addition, GPR75-deficient mice do not exhibit an increase in fat volume or a decrease in lean/muscle volume. This finding suggests that the mechanisms by which blockers of GPR75 activation prevent/reduce obesity may differ from the current therapeutics.⁵⁵

To better understand the whole potential of GPR75 as a pharmacological target in the context of metabolic syndrome, diabetes, and cardiovascular disease, it is essential to consider that pLOF variants are solely attributed to the GPR75 gene and none of its other genotypes, such as its read-through gene GPR75-ASB3. GPR75 is broken down into 2 different exons, the first being an untranslated sequence and the second being the entire translated aspect of GPR75, making it strictly specific to the GPR75 gene.⁵⁴ About 45 of 46 variants in GPR75 were associated with lower BMI, mapped to exon 2, as determined by Akbari et al.⁵⁴ These findings strongly point to an association between lower BMI and pLOF variants being solely due to the GPR75 gene.⁵⁴

As previously mentioned, in the United States, pharmacological interventions aimed at losing weight are currently dominated using GLP-1. Although initially promising, recent data show that weight loss includes lean body mass and muscle loss. Patients on these medications are advised to participate in ongoing exercise to prevent sarcomere loss. The holy grail of weight loss is reducing weight, improving insulin sensitivity, reducing oxidant stress, and decreasing hypertension, all components of the metabolic syndrome. Targeting GPR75 seems a viable alternative that might allow for such goals to be achieved and potentially prevent cardiovascular complications without losing lean body muscle mass.^56,57

CONCLUSIONS

The widespread impact of metabolic syndrome continues to affect people around the globe at an unchecked rate, leaving patients at high risk of suffering health complications and placing an increased burden on health systems and productivity. There is an urgent need for alternative ways to impact global health, with a necessary shift in focus to preventative medicine. Therapeutic targets for targeting hypertension and obesity are at the forefront, with recent advancements revealing new therapeutic targets. Whole exome gene sequencing of over 640,000 people revealed 16 genes associated with BMI, with GPR75 being the gene with the strongest correlation to lower BMI. The Schwartzman group was the first to identify this eicosanoid acting in collaboration with a GPR, with GPR as the first identified 20-HETE receptor.

GPR75 knockout animal models tend to weigh less and are at a lower risk for developing obesity. Since 20-HETE promotes hypertension and obesity via increased ACE expression, endothelial dysfunction, contractility, vascular remodeling, insulin resistance, and inflammatory cytokine production, identifying its receptor, GPR75, has opened the door for genomic therapeutic drug targeting. GPR75 discovery led to a better understanding of the influence of genetics on metabolic syndrome and represents an unprecedented opportunity for pharmacological intervention in treating the metabolic syndrome and its vascular and metabolic complications. Targeting the gene GPR75 will be safer, longer lasting, and will not have the side effects of loss of lean body muscle mass like we are experiencing with our current GLP-1RA drugs.