OR4M1

OR4M1 is an olfactory G protein-coupled receptor that functions outside the olfactory epithelium as the hepatic receptor for asprosin, the C-terminal cleavage product of profibrillin, coupling its activation to cAMP signaling to drive hepatic glucose production (PMID:32198197). Upon asprosin binding, OR4M1 signals through the cAMP/PKA axis to induce the gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; blockade of the asprosin binding site lowers cAMP, PKA activity, and these gluconeogenic enzymes, establishing OR4M1 as the upstream node of this circuit (PMID:39821628). Hepatic loss of the receptor (knockdown of the mouse ortholog Olfr734) disrupts adaptive postprandial glucose production and increases hepatic lipid content, identifying OR4M1 as a regulator of both glucose metabolism and lipid homeostasis (PMID:40806011). Independently, pharmacological activation of OR4M1 attenuates abnormal tau phosphorylation at the AT8 (Ser202/Thr205) and AT100 (Thr212/Ser214) epitopes in transgenic neuronal cultures through modulation of JNK signaling (PMID:26910498).

1. 2013 Low

   First linked OR4M1 activity to a neuronal protective phenotype, raising the question of whether this olfactory receptor influences pathological tau phosphorylation outside the olfactory system.

   Evidence OR4M1 activation in PBMC and brain tissue from traumatic brain injury subjects with JNK pathway analysis

   PMID:23241557

   Open questions at the time

   • Mechanism described only as 'possibly through JNK'
   • No in vitro reconstitution, ligand definition, or mutagenesis
   • Receptor-dependence not established
2. 2016 Medium

   Established that OR4M1 activation is causally required for the anti-tau-phosphorylation effect by using a defined ligand in receptor-expressing versus receptor-null neurons.

   Evidence Pharmacological activation with computationally identified ligand ZINC10915775 in NSE-OR4M1 transgenic versus wild-type mouse neuronal cultures, with site-specific phospho-tau antibodies and in silico homology modeling

   PMID:26910498

   Open questions at the time

   • Effect restricted to AT8/AT100 epitopes, not PHF-1 (Ser396/404)
   • JNK modulation inferred, not directly demonstrated as the intermediary
   • Single lab, transgenic overexpression system
3. 2020 Medium

   Consolidated OR4M1 as the hepatic receptor for the hormone asprosin and placed it upstream of cAMP signaling in glucose metabolism.

   Evidence Review synthesizing genetic and biochemical studies of the asprosin-OR4M1 interaction and cAMP activation in liver

   PMID:32198197

   Open questions at the time

   • Review-level synthesis, not primary data in this entry
   • Direct binding stoichiometry and receptor coupling not detailed
   • Tissue specificity of expression not resolved
4. 2022 Low

   Extended asprosin-OR4M1 signaling readouts beyond cAMP by detecting ERK1/2 phosphorylation in a non-hepatic cancer cell line.

   Evidence Western blot for ERK1/2 phosphorylation in SKOV-3 ovarian cancer cells treated with 100 nM asprosin, plus RNA sequencing

   PMID:36233808

   Open questions at the time

   • OR4M1 identity as the receptor mediating the ERK effect not directly confirmed
   • Single cell line
   • Link between ERK signaling and hepatic phenotype unestablished
5. 2025 Medium

   Demonstrated by loss of function that hepatic OR4M1 is required for adaptive glucose production and restraint of lipid accumulation, connecting the receptor to whole-organ metabolic homeostasis.

   Evidence Liver-specific Olfr734 knockdown in diet-induced obese mice with glucose metabolism and MASLD assays, corroborated by human T2DM liver biopsy data

   PMID:40806011

   Open questions at the time

   • Knockdown rather than complete knockout
   • Single lab
   • Mechanistic link between lipid accumulation and asprosin/cAMP signaling not dissected
6. 2025 Medium

   Mapped the asprosin-OR4M1 signal to the cAMP/PKA/gluconeogenic-enzyme axis by pharmacologically blocking the binding site and tracing the downstream effectors.

   Evidence Molecular docking of citronellal to OR4M1 and in vivo treatment in an HFD/STZ rat model measuring cAMP, PKA, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase

   PMID:39821628

   Open questions at the time

   • Docking-based binding-site block not validated by direct binding assay
   • Citronellal effects may include off-target actions
   • G protein coupling specificity not directly resolved

• How a single olfactory receptor reconciles its hepatic asprosin/cAMP glucose-metabolic role with its neuronal JNK/tau-modulating role, and which endogenous ligands and G protein couplings operate in each context, remains unresolved.
• No structural or biochemical characterization of direct asprosin binding
• Relationship between cAMP and ERK/JNK branches unestablished
• Endogenous neuronal ligand unidentified