Affinage

GPR75

Probable G-protein coupled receptor 75 · UniProt O95800

Length
540 aa
Mass
59.4 kDa
Annotated
2026-06-10
36 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR75 is a rhodopsin-like G protein-coupled receptor that couples to Gαq/11 and serves as a central node linking lipid signaling to body-weight regulation and cardiovascular/metabolic disease (PMID:28325781, PMID:34210852, PMID:39137039). It was identified as the high-affinity receptor for the vasoactive lipid 20-HETE (KD ~160 pM), which triggers Gαq/11 dissociation, inositol phosphate accumulation, calcium flux, and β-arrestin recruitment, with Thr212 required for ligand-dependent activation (PMID:28325781, PMID:33974269); the chemokine CCL5 binds with lower affinity but fails to activate the receptor and instead negatively regulates 20-HETE signaling (PMID:33974269). Downstream, 20-HETE-bound GPR75 recruits GIT1 and drives parallel Gαq/11–GIT1–PKCα–MaxiKβ and GIT1–c-Src–EGFR–NF-κB cascades that mediate vasoconstriction, endothelial dysfunction, and pro-inflammatory and pro-metastatic responses across vascular smooth muscle, microglia, and prostate cancer cells (PMID:28325781, PMID:31760076, PMID:35323151, PMID:39541047). In the CNS, GPR75 is expressed almost exclusively in the brain, where it localizes to the primary cilia of hypothalamic glutamatergic (vGlut2+) neurons and acts within a leptin- and ADCY3-dependent pathway to promote food intake; cell-type-restricted deletion and reactivation establish vGlut2+ neurons as the functionally critical site (PMID:39137039, PMID:41722047). Loss-of-function in humans and knockout in mice confer protection from diet-induced obesity, insulin resistance, and hepatic steatosis, principally by reducing caloric intake (PMID:34210852, PMID:38653246, PMID:41576172), while peripheral hepatic GPR75 additionally drives MASH by suppressing the GNAI2–cAMP–PKA axis to promote SREBP-1c-driven lipogenesis (PMID:41632920). Cryo-EM shows GPR75 adopts an active-like conformation with a collapsed extracellular orthosteric pocket, a non-canonical HRL (rather than DRY) motif, and a stabilizing Lys134–Asp210 salt bridge (PMID:41545757).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2017 High

    Establishing the orphan receptor's ligand and signaling output: GPR75 was identified as the 20-HETE receptor, defining the molecular cascade by which this lipid drives vascular dysfunction and hypertension.

    Evidence Chemical crosslinking, binding and functional signaling assays in endothelial and vascular smooth muscle cells, siRNA knockdown, and an in vivo mouse hypertension model

    PMID:28325781

    Open questions at the time
    • Did not resolve binding kinetics or the ligand-binding residues
    • G protein selectivity beyond Gαq/11 not addressed
  2. 2019 Medium

    Extended the 20-HETE/GPR75 axis beyond the vasculature, showing it drives pro-metastatic EGFR/NF-κB/AKT signaling in prostate cancer cells.

    Evidence Cellular EMT/invasion/migration assays with siRNA knockdown and pharmacological antagonism in PC-3 cells

    PMID:31760076

    Open questions at the time
    • Single cell line and single lab
    • No in vivo tumor metastasis validation
  3. 2021 High

    Quantified ligand engagement and identified an active-site residue: defined picomolar 20-HETE affinity, mapped Thr212 as essential for activation, and reclassified CCL5 as a non-activating negative regulator.

    Evidence Surface plasmon resonance, calcium/IP-1/β-arrestin functional assays, computational modeling, and Thr212 site-directed mutagenesis

    PMID:33974269

    Open questions at the time
    • Physiological role of CCL5 antagonism in vivo unresolved
    • Full ligand-binding pocket geometry inferred computationally, not by structure
  4. 2021 High

    Connected GPR75 to human physiology at population scale: loss-of-function variants lower BMI and obesity risk, with mouse knockout recapitulating resistance to diet-induced weight gain.

    Evidence Exome sequencing of 645,626 individuals and Gpr75 knockout mice on high-fat diet

    PMID:34210852

    Open questions at the time
    • Tissue and cell type mediating the metabolic effect not defined
    • Endogenous activating ligand in the obesity pathway not established
  5. 2022 Medium

    Dissected the effector architecture in tissue, mapping the parallel Gαq/11–GIT1–PKCα–MaxiKβ and GIT1–c-Src–EGFR branches activated by 20-HETE.

    Evidence Reciprocal co-immunoprecipitation from rat arterial tissue with 20-HETE mimetic and antagonist controls

    PMID:35323151

    Open questions at the time
    • Stoichiometry and order of complex assembly not resolved
    • Single lab, tissue-level associations only
  6. 2022 Medium

    Linked GPR75 to androgen receptor biology, showing 20-HETE/GPR75 increases AR expression, nuclear localization, and transcriptional activity in prostate cancer.

    Evidence Western blot, immunofluorescence, reporter assay, knockdown, antagonism, and LNCaP xenograft

    PMID:36202260

    Open questions at the time
    • Mechanistic link between receptor signaling and AR regulation not defined
    • Single lab
  7. 2023 Medium

    Refined the metabolic phenotype, demonstrating Gpr75 loss preserves energy expenditure, reduces adiposity and adipose inflammation, and prevents insulin resistance on HFD.

    Evidence Metabolic phenotyping of KO and heterozygous mice with adipose gene expression and insulin signaling assays

    PMID:36854900

    Open questions at the time
    • Did not separate central from peripheral contributions
    • Single lab
  8. 2023 Medium

    Revealed a non-metabolic CNS requirement: GPR75 is necessary for cone photoreceptor maintenance, independent of its oxidative-stress phenotype.

    Evidence Retinal histology, electroretinography, immunohistochemistry, and dark-housing experiments in Gpr75 KO mice

    PMID:37840219

    Open questions at the time
    • Molecular mechanism of cone maintenance unknown
    • Ligand or signaling pathway in photoreceptors not identified
  9. 2023 Medium

    Defined a vascular role in pulmonary hypertension and a cAMP-PKA effector branch: GPR75 loss raises pulmonary cAMP and blunts hypoxia-induced contraction, with CCL5 enhancing contraction GPR75-dependently.

    Evidence Global and endothelial-specific KO mice under chronic hypoxia, ex vivo contraction assays, and cAMP measurement

    PMID:37742819

    Open questions at the time
    • Reconciliation of CCL5 as activator here versus negative regulator elsewhere unresolved
    • Single lab
  10. 2024 High

    Localized the obesity-relevant receptor: GPR75 is brain-restricted and ciliary in hypothalamic neurons, signals via Gαq after HFD, and acts within a leptin/ADCY3-dependent pathway controlling food intake; BMI-lowering variants fail ciliary targeting.

    Evidence 3xFlag knock-in imaging, L144P mutagenesis, Gαq Co-IP, pair-feeding, and epistasis with Lepob and Adcy3 mutants

    PMID:39137039

    Open questions at the time
    • Endogenous ciliary ligand not identified
    • Mechanistic basis for ciliary trafficking failure of variants not defined
  11. 2024 Medium

    Confirmed central appetite control as the protective mechanism, with single-cell data placing Gpr75 with appetite-regulating hypothalamic neurons and KO preventing NAFLD via caloric adjustment.

    Evidence CRISPR-Cas9 KO mice on western diet, single-cell transcriptomics, energy balance measurements, and UK Biobank exome analysis

    PMID:38653246

    Open questions at the time
    • Specific neuronal subtype not yet functionally isolated
    • Single lab
  12. 2024 Medium

    Extended ligand-stabilization mechanism and microglial inflammation: 20-HETE binds GPR75 and inhibits its degradation, driving Src/EGFR/NF-κB activation after brain injury.

    Evidence DARTS binding, cycloheximide chase, autodock, lentiviral silencing/overexpression, and a TBI model

    PMID:39541047

    Open questions at the time
    • Degradation machinery acting on GPR75 not identified
    • Single lab
  13. 2025 Medium

    Identified an intracellular interaction partner, AMPK, through which GPR75 suppresses mitochondrial homeostasis in neurons and promotes pyroptosis/apoptosis.

    Evidence Co-IP, colocalization, knockdown, and AICAR rescue in HT22 cells and an STZ diabetic model

    PMID:41043317

    Open questions at the time
    • Direct versus indirect GPR75–AMPK interaction not resolved
    • Reciprocal validation and structural basis lacking
  14. 2025 Medium

    Linked GPR75 to hepatocyte lipid metabolism via AMPK–SIRT1, with knockdown reducing and overexpression enhancing lipid synthesis.

    Evidence Huh7 knockdown/overexpression with lipid loading, oil red O, and AMPK-SIRT1 pathway inhibitor rescue plus HFD rat model

    PMID:40728546

    Open questions at the time
    • Relationship of this axis to the GNAI2–cAMP–PKA hepatic mechanism unresolved
    • Single lab
  15. 2025 Medium

    Provided a first structural view and a discordant signaling readout: unliganded GPR75 is active-like with ECL2 occupying the orthosteric pocket, shows constitutive Gαi1 coupling without Gαq recruitment, and no measurable 20-HETE or CCL5 response.

    Evidence Cryo-EM (ICL3-BRIL fusion), ECL2 mutagenesis, and G-protein and ligand functional assays (preprint)

    PMID:bio_10.1101_2025.07.30.667585

    Open questions at the time
    • Preprint, single lab
    • Contradicts established Gαq coupling and 20-HETE activity; discrepancy unresolved
  16. 2026 High

    Pinpointed the responsible neurons: GPR75 in glutamatergic (vGlut2+), not GABAergic, neurons mediates HFD-induced weight gain, with reactivation in vGlut2+ cells fully restoring the phenotype.

    Evidence Cre-dependent conditional KO and reactivation models using vGlut2-Cre and VGAT-Cre crosses on HFD

    PMID:41722047

    Open questions at the time
    • Endogenous activating signal in vGlut2+ neurons unidentified
    • Downstream neuronal effectors of feeding control not mapped
  17. 2026 Medium

    Partitioned central versus peripheral metabolic functions: brain deletion confers obesity resistance mainly via reduced food intake, while adipocyte deletion has distinct, modest, intake-independent effects.

    Evidence Humanized floxed mouse with Nestin-Cre and adipocyte-specific KO, metabolic cages, and BAT oxygen consumption assays

    PMID:41576172

    Open questions at the time
    • Mechanism of adipocyte-autonomous effect not resolved
    • Single lab
  18. 2026 Medium

    Established a tissue-autonomous hepatic disease mechanism: hepatic GPR75 promotes MASH by suppressing GNAI2–cAMP–PKA to enhance SREBP-1c lipogenesis, and is stabilized at the membrane by VPS35.

    Evidence Hepatocyte-specific KO and overexpression mice, Western blots for GNAI2/cAMP/PKA/SREBP-1c, lipogenesis assays, and VPS35 interaction studies

    PMID:41632920

    Open questions at the time
    • Ligand driving hepatic GPR75 signaling not defined
    • Single lab
  19. 2026 Medium

    Defined a peripheral, intake-independent adipocyte role: adipocyte-specific KO protects against weight gain and the diabetogenic phenotype via increased activity and energy expenditure.

    Evidence Adipocyte-specific KO mice with metabolic cages, glucose tolerance tests, and skeletal-muscle insulin signaling assays

    PMID:41707065

    Open questions at the time
    • Adipocyte signaling pathway not delineated
    • Sex-specific weight effect not mechanistically explained
  20. 2026 High

    Resolved the structural basis of constitutive activity: cryo-EM of apo and Gq-coupled GPR75 reveals a collapsed orthosteric pocket, an HRL-for-DRY motif substitution, and a Lys134–Asp210 salt bridge stabilizing the active state.

    Evidence Cryo-EM structure determination of apo and Gq-coupled states with NanoBiT/molecular-glue stabilization

    PMID:41545757

    Open questions at the time
    • How endogenous ligands engage a collapsed pocket unresolved
    • Structural correlate of the BMI-lowering ciliary-trafficking variants not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The bona fide endogenous activating ligand operating in the obesity-relevant hypothalamic pathway, and the reconciliation of conflicting G-protein coupling (Gαq vs constitutive Gαi1) and 20-HETE responsiveness reported across systems, remain unresolved.
  • No demonstrated endogenous ligand acting on ciliary hypothalamic GPR75
  • Structural studies report no 20-HETE response while binding/functional studies report picomolar activation
  • Mechanism reconciling central appetite control with peripheral hepatic and adipocyte functions not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2
Partners
AMPKCCL5EGFRGIT1GNAQSRCVPS35

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 GPR75 is the receptor through which 20-HETE (20-hydroxyeicosatetraenoic acid) signals: 20-HETE binds GPR75, stimulates Gαq/11 protein dissociation, increases inositol phosphate accumulation, and promotes GPCR-kinase interacting protein-1 (GIT1)–GPR75 binding, which facilitates c-Src-mediated transactivation of EGFR, inducing angiotensin-converting enzyme expression and endothelial dysfunction. In vascular smooth muscle cells, GPR75–20-HETE pairing drives Gαq/11- and GIT1-mediated PKC-stimulated phosphorylation of MaxiKβ, linking GPR75 activation to vasoconstriction. GPR75 knockdown in a 20-HETE-dependent hypertension mouse model prevented blood pressure elevation. Crosslinking analogs, click chemistry, binding assays, co-immunoprecipitation, functional signaling assays in human endothelial and vascular smooth muscle cells, siRNA knockdown, in vivo mouse hypertension model Circulation research High 28325781
2021 20-HETE binds GPR75 with high affinity (KD ~1.56×10⁻¹⁰ M) as measured by surface plasmon resonance. In GPR75-transfected cells, 20-HETE stimulates intracellular Ca²⁺ elevation, IP-1 accumulation, and β-arrestin recruitment. Mutation of Thr212 within the putative 20-HETE binding site abolished 20-HETE-stimulated GPR75 activation. CCL5 binds GPR75 with lower affinity (KD ~5.85×10⁻¹⁰ M) but fails to activate it; instead CCL5 acts as a negative regulator, inhibiting 20-HETE-induced GPR75 signaling. Surface plasmon resonance (SPR), FLIPR calcium assay, HTRF IP-1 assay, β-arrestin recruitment assay (PRESTO-Tango), computational modelling, site-directed mutagenesis (Thr212), siRNA knockdown in human endothelial cells British journal of pharmacology High 33974269
2021 Loss-of-function (protein-truncating) variants in GPR75 are associated with ~1.8 kg/m² lower BMI and 54% lower odds of obesity in humans. Knockout of Gpr75 in mice confers resistance to weight gain and improved glycemic control on high-fat diet. Exome sequencing of 645,626 individuals; mouse Gpr75 knockout on high-fat diet Science (New York, N.Y.) High 34210852
2019 GPR75 mediates 20-HETE-induced pro-metastatic signaling in androgen-insensitive prostate cancer cells (PC-3): 20-HETE (0.1 nM) promoted EMT, MMP-2 release, cell migration/invasion, actin stress fiber formation, and anchorage-independent growth via EGFR, NF-κB, AKT, and p38 phosphorylation. These effects were abrogated by GPR75 antagonism and/or siRNA silencing of GPR75. Western blot, fluorescence microscopy, EMT assay, MMP-2 gelatin zymography, scratch wound healing, transwell invasion, soft agar colony formation, siRNA knockdown, pharmacological antagonism Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 31760076
2022 GPR75 signals through a Gαq/11/GIT1/PKCα/MaxiKβ and GIT1/c-Src/EGFR axis: co-immunoprecipitation in arterial tissue showed GPR75/Gαq/11 dissociation, GIT1/GPR75 association, MaxiKβ/PKCα and MaxiKβ/c-Src associations, and EGFR/c-Src association upon 20-HETE mimetic (5,14-HEDGE) treatment, all of which were reversed by a 20-HETE antagonist. Co-immunoprecipitation from rat arterial tissues, pharmacological manipulation with 20-HETE mimetic (5,14-HEDGE) and antagonist (20-HEDE), LPS septic shock rat model Journal of cardiovascular pharmacology Medium 35323151
2022 20-HETE acting through GPR75 increases androgen receptor (AR) expression, nuclear localization, and transcriptional activity in LNCaP prostate cancer cells. Chemical antagonism of GPR75 (19-HEDE) or transient GPR75 knockdown abolished these effects. Western blot, immunofluorescence for nuclear localization, transcriptional activity reporter, siRNA knockdown, pharmacological antagonism, LNCaP xenograft model Molecular and cellular endocrinology Medium 36202260
2023 Gpr75 knockout mice exhibit mild progressive retinal degeneration specifically affecting M-cone and S-cone photoreceptor cells, accompanied by oxidative stress, establishing GPR75 as required for cone photoreceptor cell maintenance. Constant dark housing reduced oxidative stress but did not prevent cone loss, indicating oxidative stress is not the primary cause. Gpr75 knockout mouse retinal characterization, histology, electroretinography, immunohistochemistry, dark housing experiment Journal of neurochemistry Medium 37840219
2023 Gpr75-deficient mice (KO and heterozygous) gain less weight than WT on high-fat diet. KO mice maintained energy expenditure (WT showed significant reduction), had reduced adiposity and adipocyte hypertrophy, did not develop insulin resistance, showed increased thermogenic gene expression and decreased inflammatory markers in adipose tissue, and had preserved insulin signaling. Gpr75 KO and heterozygous mouse metabolic phenotyping on HFD, energy expenditure measurement, adipose tissue gene expression, insulin signaling assays Obesity (Silver Spring, Md.) Medium 36854900
2024 GPR75 is exclusively expressed in the brain of knock-in mice (3xFlag-tagged Gpr75), and is localized to primary cilia of hypothalamic cells. The Thinner missense allele (L144P) and human GPR75 variants associated with lower BMI failed to localize to cilia. GPR75 interacts with Gαq to activate signaling after HFD. Loss of GPR75 reduced food intake under HFD, and pair-feeding normalized body weight in KO mice. GPR75 KO failed to suppress obesity in leptin ob-mutant or Adcy3-mutant mice on chow, placing GPR75 in a pathway requiring intact leptin and adenylate cyclase 3 signaling. Random germline mutagenesis, 3xFlag knock-in mice, immunofluorescence/confocal microscopy for ciliary localization, Co-IP for Gαq interaction, Gpr75-KO phenotyping, pair-feeding experiments, epistasis with Lepob and Adcy3 mutants The Journal of clinical investigation High 39137039
2024 GPR75 CRISPR-Cas9 knockout in mice fed a western diet prevents NAFLD by adjusting caloric intake to maintain energy balance. Gpr75 is most abundantly expressed in the brain, and single-cell analysis identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9 KO mice, western diet feeding, single-cell transcriptomics, energy balance measurements, human UK Biobank exome-sequencing analysis Cell metabolism Medium 38653246
2023 GPR75 global and endothelial-cell-specific knockout mice are protected from hypoxia-induced pulmonary hypertension: chronic hypoxia increased right ventricular pressures in WT but not Gpr75-/- or EC-Gpr75-/- mice. GPR75 expression increased in alveoli, airways, and pulmonary arteries under hypoxia. CCL5 (a low-affinity GPR75 ligand) enhanced hypoxia-induced pulmonary artery contraction in a GPR75-dependent manner. GPR75 KO increased pulmonary cAMP levels and decreased endothelin-1/U46619-evoked contraction via a cAMP-PKA-dependent mechanism. Global and endothelial-specific Gpr75 KO mice, hypoxia exposure (10% O₂, 5 weeks), echocardiography, right heart catheterization, in situ hybridization, qPCR, ex vivo pulmonary artery contraction assays, cAMP measurement Vascular pharmacology Medium 37742819
2024 20-HETE binds GPR75 (confirmed by DARTS and autodock assays) and inhibits GPR75 protein degradation. In BV-2 microglial cells, GPR75 silencing reversed 20-HETE-induced inflammatory activation and inhibited the Src/EGFR/NF-κB pathway. GPR75 overexpression had the opposite effect. After immature brain TBI, 20-HETE and GPR75 expression were upregulated in microglia with Src/EGFR/NF-κB pathway activation. DARTS assay, cycloheximide chase assay, autodock simulation, lentivirus-mediated GPR75 silencing and overexpression, ELISA for inflammatory factors, Western blot for pathway components, CCK-8 viability and TUNEL apoptosis assays, immunofluorescence in TBI model Neurochemical research Medium 39541047
2025 GPR75 interacts with and inhibits AMPK in hippocampal neurons: co-localization and co-immunoprecipitation confirmed GPR75–AMPK interaction in HT22 cells. GPR75 upregulation inhibits AMPK-mediated mitochondrial homeostasis, causing impaired mitochondrial dynamics, disrupted energy metabolism, elevated ROS, and triggering pyroptosis and apoptosis. AMPK activator AICAR mitigated GPR75-induced mitochondrial dysfunction. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown in HT22 cells and STZ diabetic mouse model, mitochondrial function assays, ROS measurement, pyroptosis/apoptosis assays, AICAR rescue experiment International immunopharmacology Medium 41043317
2025 GPR75 knockdown reduces lipid synthesis and improves lipid metabolism in hepatocytes via activation of the AMPK–SIRT1 signaling pathway; inhibiting AMPK–SIRT1 after GPR75 knockdown reverses these metabolic improvements. GPR75 overexpression markedly enhances lipid synthesis and impairs metabolism. Huh7 cell overexpression and knockdown, palmitic acid/oleic acid lipid loading model, oil red O staining, immunofluorescence, Western blot for FASN, SREBP1, AMPK, SIRT1; HFD rat model; AMPK-SIRT1 pathway inhibition rescue Molecular biotechnology Medium 40728546
2026 Cryo-EM structures of human GPR75 in apo and Gq-coupled states reveal: (1) a completely collapsed extracellular domain eliminating the traditional orthosteric binding pocket; (2) the canonical DRY motif is replaced by HRL, abolishing the ionic lock; (3) a distinctive Lys134–Asp210 salt bridge stabilizes the active conformation without ligand binding; (4) GPR75 adopts an active-like conformation in both apo and G-protein-complexed states. Cryo-EM structure determination using NanoBiT and molecular glue stabilization approaches, structural analysis of apo and Gq-coupled states Acta pharmacologica Sinica High 41545757
2025 Cryo-EM structure of unliganded human GPR75 shows it adopts an active-like state driven by ECL2 folding deeply into the orthosteric pocket. Mutagenesis studies confirmed ECL2 is important for both receptor integrity and signaling. GPR75 shows moderate constitutive activity for Gαi1, while Gαq is not recruited. Functional assays showed 20-HETE and CCL5 have no measurable effect on GPR75 signaling in this system. Cryo-EM (ICL3-BRIL fusion), site-directed mutagenesis of ECL2, G-protein coupling functional assays for Gαi1 and Gαq, ligand functional assays (20-HETE, CCL5) bioRxivpreprint Medium bio_10.1101_2025.07.30.667585
2026 Loss of GPR75 specifically in glutamatergic (vGlut2+) neurons protects against HFD-induced weight gain and reduces food intake without changing energy expenditure. Loss of GPR75 in GABAergic neurons had no effect on diet-induced obesity. Reactivation of GPR75 only in vGlut2+ cells of a Gpr75-null mouse fully rescued HFD-induced weight gain; reactivation in GABAergic cells had no effect. Cre-dependent conditional Gpr75 knockout and reactivation mouse models, vGlut2-Cre and VGAT-Cre crosses, HFD feeding, food intake and energy expenditure measurement Cell reports High 41722047
2026 Brain-specific Gpr75 deletion (Nestin-Cre) in a humanized floxed mouse model confers resistance to diet-induced obesity primarily through suppressed food intake and modest increases in energy expenditure. Adipocyte-specific Gpr75 deletion had minimal effects on systemic metabolism but modestly enhanced mitochondrial oxygen consumption in brown adipose tissue under cold exposure. Humanized floxed Gpr75 mouse model, Nestin-Cre brain-specific and adipocyte-specific conditional KO, HFD feeding, metabolic cage measurements, mitochondrial oxygen consumption assay, histology and transcriptomics Science advances Medium 41576172
2026 Hepatic GPR75 promotes MASH: hepatocyte-specific Gpr75 overexpression exacerbated diet-induced MASH and liver fibrosis, while whole-liver or hepatocyte-specific Gpr75 depletion protected mice from diet-induced hepatic steatosis. Mechanistically, hepatic Gpr75 deficiency activated the GNAI2–cAMP–PKA signaling pathway, reducing SREBP-1c maturation and de novo lipogenesis. VPS35 stabilizes GPR75 by recycling it to the hepatocyte membrane. Hepatocyte-specific Gpr75 KO and overexpression mouse models, Western blot for GNAI2/cAMP/PKA/SREBP-1c, de novo lipogenesis assays, VPS35 interaction studies Hepatology (Baltimore, Md.) Medium 41632920
2026 Adipocyte-specific Gpr75 knockout protects female mice from HFD-induced weight gain (50% decrease) and protects both sexes from diabetogenic phenotype, with improved glucose handling, abrogated adipose tissue inflammation, and increased insulin sensitivity in skeletal muscle. Adipo-Gpr75-/- mice showed increased activity and energy expenditure without changes in food intake, indicating a peripheral (non-CNS) metabolic mechanism. Adipocyte-specific Gpr75 KO mouse model, HFD feeding, metabolic cage measurements (food intake, energy expenditure, activity), glucose tolerance tests, adipose tissue inflammation markers, insulin signaling in skeletal muscle FASEB journal Medium 41707065
2025 20-HETE-induced platelet activation is independent of GPR75: GPR75 knockout mice showed no difference in 20-HETE-mediated platelet aggregation, granule release, or integrin αIIbβ3 activation compared to WT. The effects of 20-HETE on platelets are mediated through other Gαq-coupled GPCRs. GPR75 knockout mice, human platelet aggregation assays, GPR75 antagonist (20-HEDE), platelet granule secretion and integrin activation assays Thrombosis research Medium 39914277

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science (New York, N.Y.) 228 34210852
2017 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circulation research 162 28325781
2021 Uncovering the signalling, structure and function of the 20-HETE-GPR75 pairing: Identifying the chemokine CCL5 as a negative regulator of GPR75. British journal of pharmacology 42 33974269
2019 GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 39 31760076
2023 Gpr75-deficient mice are protected from high-fat diet-induced obesity. Obesity (Silver Spring, Md.) 32 36854900
2024 Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation. Cell metabolism 31 38653246
2001 Evaluation of the G protein coupled receptor-75 (GPR75) in age related macular degeneration. The British journal of ophthalmology 29 11466257
2022 The CYP/20-HETE/GPR75 axis in hypertension. Advances in pharmacology (San Diego, Calif.) 24 35659370
2024 Central regulation of feeding and body weight by ciliary GPR75. The Journal of clinical investigation 19 39137039
2023 G Protein-Coupled Receptor 75 (GPR75) As a Novel Molecule for Targeted Therapy of Cancer and Metabolic Syndrome. Asian Pacific journal of cancer prevention : APJCP 19 37247305
2024 20-Hydroxyeicosatetraenoic Acid Regulates the Src/EGFR/NF-κB Signaling Pathway Via GPR75 to Activate Microglia and Promote TBI in the Immature Brain. Neurochemical research 12 39541047
2023 Advanced nano-therapeutic delivery of metformin: potential anti-cancer effect against human colon cancer cells through inhibition of GPR75 expression. Medical oncology (Northwood, London, England) 12 37515667
2022 GPR75: An exciting new target in metabolic syndrome and related disorders. Biochimie 12 35045335
2022 Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock. Journal of cardiovascular pharmacology 11 35323151
2023 Gpr75 knockout mice display age-dependent cone photoreceptor cell loss. Journal of neurochemistry 10 37840219
2022 20-HETE/GPR75 pairing modulates the expression and transcriptional activity of the androgen receptor in androgen-sensitive prostate cancer cells. Molecular and cellular endocrinology 9 36202260
2025 The CYP4/20-HETE/GPR75 axis in the progression metabolic dysfunction-associated steatosis liver disease (MASLD) to chronic liver disease. Frontiers in physiology 8 39959811
2023 Global and endothelial G-protein coupled receptor 75 (GPR75) knockout relaxes pulmonary artery and mitigates hypoxia-induced pulmonary hypertension. Vascular pharmacology 7 37742819
2025 Adopting GPR75 in treating obesity: unraveling the knowns and unknowns of this orphan GPCR. Trends in cell biology 5 39794254
2024 GPR75: A Newly Identified Receptor for Targeted Intervention in the Treatment of Obesity and Metabolic Syndrome. Cardiology in review 4 38695569
2023 Pro-inflammatory GPR75 and anti-apoptotic phospholipase signaling pathways contribute to the ameliorating effect of soluble epoxide hydrolase inhibition on chronic experimental autoimmune encephalomyelitis in mice. Cellular and molecular biology (Noisy-le-Grand, France) 4 37953590
2025 GPR75: Advances, Challenges in Deorphanization, and Potential as a Novel Drug Target for Disease Treatment. International journal of molecular sciences 3 40362321
2024 Whole-genome resequencing and RNA-seq analysis implicates GPR75 as a potential genetic basis related to retarded growth in South China carp (Cyprinus carpio rubrofuscus). Genomics 3 39236771
2025 20-HETE induced platelet activation via a GPR75-independent pathway. Thrombosis research 2 39914277
2025 Inhibition of GPR75 Alleviates Lipid Metabolism by Activating the AMPK-SIRT1 Signaling Pathway In Vitro and In Vivo. Molecular biotechnology 2 40728546
2025 GPR75 knockdown alleviates mitochondrial dysfunction in hippocampal neurons via AMPK pathway in diabetic mice. International immunopharmacology 2 41043317
2025 GPR75 signaling is dispensable for reproduction but contributes to feeding and body growth in rats on normal chow and is involved in high-fat diet-induced hyperphagia, obesity, and hyperglycemia development. Endocrine journal 2 41062295
2026 Neuronal GPR75 deficiency protects against diet-induced obesity in a humanized mouse model. Science advances 1 41576172
2024 Effect and mechanism of GPR75 in metabolic dysfunction-related steatosis liver disease. International journal of medical sciences 1 39310267
2026 Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target. Acta pharmacologica Sinica 0 41545757
2026 Hepatic GPR75 exacerbates MASH through GNAI2-dependent signaling. Hepatology (Baltimore, Md.) 0 41632920
2026 Gpr75 Deletion in Adipocytes Protects From Diet-Induced Obesity: Changes in Glucose Homeostasis and Inflammatory Responses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41707065
2026 GPR75 in glutamatergic neurons regulates body weight. Cell reports 0 41722047
2026 Antagonism of GPR75 inhibits gestational diabetes mellitus-induced placental tissue injury by preventing activation of the NLRP3 inflammasome. Tissue & cell 0 41962334
2025 CYP1A1/20-HETE/GPR75 Axis-Mediated Arachidonic Acid Metabolism Dysregulation in H-Type Hypertension Pathogenesis. International journal of molecular sciences 0 40649725
2025 Orphan G-protein coupled receptor 75 (GPR75), a unique and controversial potential therapeutic target. Journal of receptor and signal transduction research 0 40757922

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