OR4M1

OR4M1 is an olfactory G protein-coupled receptor that functions as the hepatic receptor for asprosin, coupling ligand binding to cAMP/PKA signaling to promote gluconeogenesis through induction of glucose-6-phosphatase and PEPCK (PMID:32198197, PMID:39821628). Liver-specific loss of its mouse ortholog Olfr734 worsens hepatic glucose metabolism and promotes steatosis in diet-induced obese mice, and OR4M1 expression is elevated in liver biopsies from male type 2 diabetes patients, establishing a direct role in hepatic glucose and lipid homeostasis (PMID:40806011). Beyond the liver, activation of OR4M1 in neuronal cultures attenuates abnormal tau hyperphosphorylation at specific epitopes (AT8, AT100) through modulation of JNK signaling (PMID:23241557, PMID:26910498). Asprosin-OR4M1 signaling also activates ERK1/2 phosphorylation in ovarian cancer cells, indicating pathway engagement outside hepatocytes (PMID:36233808).

1. 2013 Medium

   The first functional role for OR4M1 outside olfaction was established when its activation in neuronal cultures was shown to reduce pathological tau phosphorylation, linking an ectopic olfactory receptor to neurodegeneration-relevant signaling.

   Evidence Embryonic cortico-hippocampal cultures from NSE-OR4M1 transgenic mice; phospho-tau immunoblotting at AT8, AT100, PHF-1 epitopes

   PMID:23241557

   Open questions at the time

   • Endogenous ligand for OR4M1 in neurons not identified
   • Mechanism connecting OR4M1 to JNK pathway not delineated
   • Single transgenic overexpression system, not confirmed with endogenous receptor
2. 2016 Medium

   A synthetic agonist (ZINC10915775) identified via homology modeling selectively reduced tau phosphorylation at AT8 and AT100 but not PHF-1 epitopes, demonstrating epitope-specific signaling downstream of OR4M1 and implicating JNK as the mediating kinase.

   Evidence In silico 3-D homology model and virtual ligand screening; pharmacological activation in NSE-OR4M1 transgenic neuronal cultures with phospho-tau immunoblotting

   PMID:26910498

   Open questions at the time

   • Binding affinity of ZINC10915775 for OR4M1 not measured directly
   • JNK involvement inferred from downstream readout, not from direct kinase inhibition epistasis
   • In vivo validation of agonist effects absent
3. 2020 Medium

   Identification of asprosin as the endogenous ligand for OR4M1 resolved the receptor's physiological context, establishing it as the hepatic mediator of asprosin-driven cAMP signaling and gluconeogenesis.

   Evidence Genetic and pharmacological receptor identification studies with cAMP pathway activation readouts

   PMID:32198197

   Open questions at the time

   • Direct binding assay data (e.g., radioligand or SPR) between asprosin and OR4M1 not provided in this report
   • Relative contribution of OR4M1 versus other potential asprosin receptors not quantified
   • Findings summarized in a review context rather than primary research article
4. 2022 Medium

   Demonstration that asprosin-OR4M1 signaling activates ERK1/2 in ovarian cancer cells expanded the receptor's signaling repertoire beyond cAMP/PKA, suggesting tissue-dependent pathway engagement.

   Evidence Western blotting for ERK1/2 phosphorylation in SKOV-3 ovarian cancer cells treated with asprosin

   PMID:36233808

   Open questions at the time

   • OR4M1 dependence of ERK1/2 activation not confirmed by receptor knockdown in these cells
   • Functional consequences of ERK1/2 activation for cancer cell behavior not characterized
   • Single cell line study
5. 2025 Medium

   Pharmacological blockade of OR4M1 by citronellal in a diabetic rat model reduced cAMP, PKA activity, and gluconeogenic enzymes, providing in vivo evidence that the asprosin-OR4M1-cAMP/PKA-gluconeogenesis axis is druggable.

   Evidence Molecular docking of citronellal to OR4M1; HFD/STZ rat model with hepatic cAMP, PKA, G6Pase, and PEPCK measurements

   PMID:39821628

   Open questions at the time

   • Citronellal specificity for OR4M1 versus other olfactory receptors not validated by genetic knockout control
   • Direct competitive binding data absent; reliance on molecular docking
   • Long-term metabolic outcomes of citronellal treatment not assessed
6. 2025 High

   Liver-specific knockdown of Olfr734 (mouse OR4M1 ortholog) causally linked the receptor to hepatic glucose and lipid homeostasis, and elevated OR4M1 in human T2DM liver biopsies supported clinical relevance.

   Evidence Liver-specific genetic knockdown in diet-induced obese mice; glucose metabolism and lipid content assays; human liver biopsy expression analysis

   PMID:40806011

   Open questions at the time

   • Whether OR4M1 upregulation in human T2DM is compensatory or pathogenic is unresolved
   • Lipid accumulation mechanism downstream of OR4M1 loss not defined
   • Female-specific data not reported for human liver expression

• The structural basis of asprosin-OR4M1 interaction, the mechanism by which OR4M1 loss drives steatosis, and whether neuronal OR4M1 signaling is physiologically relevant in vivo remain unresolved.
• No co-crystal or cryo-EM structure of OR4M1 with asprosin exists
• Lipid accumulation downstream of OR4M1 deficiency has no defined molecular mechanism
• In vivo neuronal function of OR4M1 and endogenous brain ligand unknown