{"gene":"OR4M1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2013,"finding":"Activation of OR4M1 attenuated abnormal tau phosphorylation, possibly through modulation of the JNK signaling pathway, in brain cells following traumatic brain injury.","method":"OR4M1 activation in PBMC and brain tissue specimens from TBI subjects; JNK signaling pathway analysis","journal":"Journal of Alzheimer's disease : JAD","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, mechanism described as 'possibly through JNK', no in vitro reconstitution or mutagenesis; pathway placement is inferred","pmids":["23241557"],"is_preprint":false},{"year":2016,"finding":"In vitro activation of OR4M1 with ZINC library compound 10915775 significantly attenuated abnormal tau phosphorylation at Ser202/T205 (AT8) and Thr212/Ser214 (AT100) epitopes, but not Ser396/404 (PHF-1), in embryonic cortico-hippocampal neuronal cultures from NSE-OR4M1 transgenic mice, acting through modulation of the JNK signaling pathway. No effect was observed in wild-type controls lacking OR4M1.","method":"In vitro pharmacological activation of OR4M1 using a computationally-identified ligand (ZINC10915775) in NSE-OR4M1 transgenic mouse neuronal cultures; tau phosphorylation assay with site-specific antibodies; 3D in silico homology modeling of OR4M1","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay with transgenic vs. wild-type controls, multiple phospho-epitope readouts, and in silico structural model; single lab, single study","pmids":["26910498"],"is_preprint":false},{"year":2020,"finding":"Asprosin, the C-terminal cleavage product of profibrillin, exerts its hepatic glucogenic effect through OR4M1, an olfactory G-protein-coupled receptor expressed in the liver, activating the cAMP signaling circuitry.","method":"Review summarizing genetic and biochemical studies establishing asprosin-OR4M1 interaction and cAMP pathway activation in liver","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review citing experimental studies establishing OR4M1 as the hepatic asprosin receptor via cAMP pathway; not primary data in this paper but synthesizes replicated findings","pmids":["32198197"],"is_preprint":false},{"year":2022,"finding":"Asprosin promotes hepatic glucose release and appetite stimulation through activation of cAMP signaling via its G protein-coupled receptor OR4M1; asprosin also induced phosphorylation of ERK1/2 in the serous ovarian cancer cell line SKOV-3 following treatment with 100 nM asprosin.","method":"Western blotting for ERK1/2 phosphorylation in SKOV-3 cells treated with asprosin; RNA sequencing for downstream gene regulatory changes; cAMP pathway activation reviewed from prior literature","journal":"Journal of clinical medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ERK1/2 phosphorylation shown by Western blot in a single ovarian cancer cell line; OR4M1 receptor identity for this effect not directly confirmed in this study","pmids":["36233808"],"is_preprint":false},{"year":2025,"finding":"Hepatic knockdown of Olfr734 (the mouse ortholog of human OR4M1) increased hepatic lipid content in diet-induced obese mice and disrupted adaptive glucose production in response to nutrient availability, establishing OR4M1/Olfr734 as a regulator of hepatic glucose metabolism and lipid homeostasis downstream of asprosin signaling.","method":"Genetic knockdown of Olfr734 specifically in mouse liver; assessment of MASLD progression in DIO mice; glucose metabolism assays including postprandial glucose production; liver biopsy analysis from human patients with T2DM","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetic knockdown in mouse liver with defined metabolic phenotypes; corroborated by human liver biopsy data; single lab","pmids":["40806011"],"is_preprint":false},{"year":2025,"finding":"Citronellal blocked the asprosin binding site on OR4M1 (confirmed by molecular docking), reduced hepatic OR4M1 expression, lowered cAMP levels, and attenuated downstream protein kinase A and gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), demonstrating that OR4M1 signals through the cAMP/PKA axis to regulate hepatic gluconeogenesis.","method":"Molecular docking of citronellal to OR4M1; in vivo pharmacological treatment in HFD/STZ rat model; measurement of cAMP, PKA, gluconeogenic enzymes, TLR-4/JNK/NF-κB pathway components","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function pharmacology with mechanistic readouts (cAMP, PKA, gluconeogenic enzymes) supported by docking; single lab, single study","pmids":["39821628"],"is_preprint":false}],"current_model":"OR4M1 is an olfactory G protein-coupled receptor that functions as the hepatic receptor for asprosin (C-terminal cleavage product of profibrillin/FBN1), coupling asprosin binding to cAMP/PKA signaling to promote gluconeogenesis; loss of OR4M1/Olfr734 in the liver impairs adaptive glucose production and promotes hepatic lipid accumulation, and OR4M1 activation also attenuates JNK-mediated abnormal tau phosphorylation in neurons."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2013,"claim":"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","pmids":["23241557"],"confidence":"Low","gaps":["Mechanism described only as 'possibly through JNK'","No in vitro reconstitution, ligand definition, or mutagenesis","Receptor-dependence not established"]},{"year":2016,"claim":"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","pmids":["26910498"],"confidence":"Medium","gaps":["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"]},{"year":2020,"claim":"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","pmids":["32198197"],"confidence":"Medium","gaps":["Review-level synthesis, not primary data in this entry","Direct binding stoichiometry and receptor coupling not detailed","Tissue specificity of expression not resolved"]},{"year":2022,"claim":"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","pmids":["36233808"],"confidence":"Low","gaps":["OR4M1 identity as the receptor mediating the ERK effect not directly confirmed","Single cell line","Link between ERK signaling and hepatic phenotype unestablished"]},{"year":2025,"claim":"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","pmids":["40806011"],"confidence":"Medium","gaps":["Knockdown rather than complete knockout","Single lab","Mechanistic link between lipid accumulation and asprosin/cAMP signaling not dissected"]},{"year":2025,"claim":"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","pmids":["39821628"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical characterization of direct asprosin binding","Relationship between cAMP and ERK/JNK branches unestablished","Endogenous neuronal ligand unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["ASPROSIN","FBN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NGD0","full_name":"Olfactory receptor 4M1","aliases":["Olfactory receptor OR14-7"],"length_aa":313,"mass_kda":35.5,"function":"Olfactory receptor that acts as a receptor of Asprosin hormone, potentially at the surface of hepatocytes and may help to promote hepatocyte glucose release","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NGD0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OR4M1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1090,"dependency_fraction":0.001834862385321101},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OR4M1","total_profiled":1310},"omim":[{"mim_id":"619939","title":"OLFACTORY RECEPTOR, FAMILY 4, SUBFAMILY M, MEMBER 1; OR4M1","url":"https://www.omim.org/entry/619939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OR4M1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8NGD0","domains":[{"cath_id":"1.20.1070.10","chopping":"10-307","consensus_level":"high","plddt":90.9745,"start":10,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NGD0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NGD0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NGD0-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OR4M1","jax_strain_url":"https://www.jax.org/strain/search?query=OR4M1"},"sequence":{"accession":"Q8NGD0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NGD0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NGD0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NGD0"}},"corpus_meta":[{"pmid":"23241557","id":"PMC_23241557","title":"Decreased level of olfactory receptors in blood cells following traumatic brain injury and potential association with tauopathy.","date":"2013","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/23241557","citation_count":41,"is_preprint":false},{"pmid":"32198197","id":"PMC_32198197","title":"Energy Regulation Mechanism and Therapeutic Potential of Asprosin.","date":"2020","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/32198197","citation_count":33,"is_preprint":false},{"pmid":"33112803","id":"PMC_33112803","title":"Discovery of a possible role of asprosin in ovarian follicular function.","date":"2021","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33112803","citation_count":29,"is_preprint":false},{"pmid":"34386072","id":"PMC_34386072","title":"A pancancer overview of FBN1, asprosin and its cognate receptor OR4M1 with detailed expression profiling in ovarian cancer.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34386072","citation_count":27,"is_preprint":false},{"pmid":"35707591","id":"PMC_35707591","title":"Asprosin, a C-Terminal Cleavage Product of Fibrillin 1 Encoded by the FBN1 Gene, in Health and Disease.","date":"2022","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/35707591","citation_count":20,"is_preprint":false},{"pmid":"34781067","id":"PMC_34781067","title":"A potential role of fibrillin-1 (FBN1) mRNA and asprosin in follicular development in water buffalo.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34781067","citation_count":18,"is_preprint":false},{"pmid":"36233808","id":"PMC_36233808","title":"Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36233808","citation_count":12,"is_preprint":false},{"pmid":"36978520","id":"PMC_36978520","title":"Comparative Analysis of Olfactory Receptor Repertoires Sheds Light on the Diet Adaptation of the Bamboo-Eating Giant Panda Based on the Chromosome-Level Genome.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36978520","citation_count":6,"is_preprint":false},{"pmid":"37167929","id":"PMC_37167929","title":"Developmental and hormonal regulation of FBN1 and OR4M1 mRNA in bovine granulosa cells.","date":"2023","source":"Domestic animal endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37167929","citation_count":4,"is_preprint":false},{"pmid":"40871563","id":"PMC_40871563","title":"Effects of Asprosin and Role of TLR4 as a Biomarker in Endometrial Cancer.","date":"2025","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40871563","citation_count":2,"is_preprint":false},{"pmid":"26910498","id":"PMC_26910498","title":"In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy.","date":"2016","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26910498","citation_count":1,"is_preprint":false},{"pmid":"40806011","id":"PMC_40806011","title":"Hepatic Olfr734 Deficiency Worsens Hepatic Glucose Metabolism and Induces MASLD in Mice.","date":"2025","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/40806011","citation_count":1,"is_preprint":false},{"pmid":"39821628","id":"PMC_39821628","title":"Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor Axis.","date":"2025","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/39821628","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9599,"output_tokens":1671,"usd":0.026931,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8531,"output_tokens":2443,"usd":0.051865,"stage2_stop_reason":"end_turn"},"total_usd":0.078796,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Activation of OR4M1 attenuated abnormal tau phosphorylation, possibly through modulation of the JNK signaling pathway, in brain cells following traumatic brain injury.\",\n      \"method\": \"OR4M1 activation in PBMC and brain tissue specimens from TBI subjects; JNK signaling pathway analysis\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, mechanism described as 'possibly through JNK', no in vitro reconstitution or mutagenesis; pathway placement is inferred\",\n      \"pmids\": [\"23241557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vitro activation of OR4M1 with ZINC library compound 10915775 significantly attenuated abnormal tau phosphorylation at Ser202/T205 (AT8) and Thr212/Ser214 (AT100) epitopes, but not Ser396/404 (PHF-1), in embryonic cortico-hippocampal neuronal cultures from NSE-OR4M1 transgenic mice, acting through modulation of the JNK signaling pathway. No effect was observed in wild-type controls lacking OR4M1.\",\n      \"method\": \"In vitro pharmacological activation of OR4M1 using a computationally-identified ligand (ZINC10915775) in NSE-OR4M1 transgenic mouse neuronal cultures; tau phosphorylation assay with site-specific antibodies; 3D in silico homology modeling of OR4M1\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay with transgenic vs. wild-type controls, multiple phospho-epitope readouts, and in silico structural model; single lab, single study\",\n      \"pmids\": [\"26910498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Asprosin, the C-terminal cleavage product of profibrillin, exerts its hepatic glucogenic effect through OR4M1, an olfactory G-protein-coupled receptor expressed in the liver, activating the cAMP signaling circuitry.\",\n      \"method\": \"Review summarizing genetic and biochemical studies establishing asprosin-OR4M1 interaction and cAMP pathway activation in liver\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review citing experimental studies establishing OR4M1 as the hepatic asprosin receptor via cAMP pathway; not primary data in this paper but synthesizes replicated findings\",\n      \"pmids\": [\"32198197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Asprosin promotes hepatic glucose release and appetite stimulation through activation of cAMP signaling via its G protein-coupled receptor OR4M1; asprosin also induced phosphorylation of ERK1/2 in the serous ovarian cancer cell line SKOV-3 following treatment with 100 nM asprosin.\",\n      \"method\": \"Western blotting for ERK1/2 phosphorylation in SKOV-3 cells treated with asprosin; RNA sequencing for downstream gene regulatory changes; cAMP pathway activation reviewed from prior literature\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ERK1/2 phosphorylation shown by Western blot in a single ovarian cancer cell line; OR4M1 receptor identity for this effect not directly confirmed in this study\",\n      \"pmids\": [\"36233808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hepatic knockdown of Olfr734 (the mouse ortholog of human OR4M1) increased hepatic lipid content in diet-induced obese mice and disrupted adaptive glucose production in response to nutrient availability, establishing OR4M1/Olfr734 as a regulator of hepatic glucose metabolism and lipid homeostasis downstream of asprosin signaling.\",\n      \"method\": \"Genetic knockdown of Olfr734 specifically in mouse liver; assessment of MASLD progression in DIO mice; glucose metabolism assays including postprandial glucose production; liver biopsy analysis from human patients with T2DM\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetic knockdown in mouse liver with defined metabolic phenotypes; corroborated by human liver biopsy data; single lab\",\n      \"pmids\": [\"40806011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Citronellal blocked the asprosin binding site on OR4M1 (confirmed by molecular docking), reduced hepatic OR4M1 expression, lowered cAMP levels, and attenuated downstream protein kinase A and gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), demonstrating that OR4M1 signals through the cAMP/PKA axis to regulate hepatic gluconeogenesis.\",\n      \"method\": \"Molecular docking of citronellal to OR4M1; in vivo pharmacological treatment in HFD/STZ rat model; measurement of cAMP, PKA, gluconeogenic enzymes, TLR-4/JNK/NF-κB pathway components\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function pharmacology with mechanistic readouts (cAMP, PKA, gluconeogenic enzymes) supported by docking; single lab, single study\",\n      \"pmids\": [\"39821628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OR4M1 is an olfactory G protein-coupled receptor that functions as the hepatic receptor for asprosin (C-terminal cleavage product of profibrillin/FBN1), coupling asprosin binding to cAMP/PKA signaling to promote gluconeogenesis; loss of OR4M1/Olfr734 in the liver impairs adaptive glucose production and promotes hepatic lipid accumulation, and OR4M1 activation also attenuates JNK-mediated abnormal tau phosphorylation in neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#2]. 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 [#5]. 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 [#4]. 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 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"OR4M1 activation in PBMC and brain tissue from traumatic brain injury subjects with JNK pathway analysis\",\n      \"pmids\": [\"23241557\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism described only as 'possibly through JNK'\", \"No in vitro reconstitution, ligand definition, or mutagenesis\", \"Receptor-dependence not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"26910498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Consolidated OR4M1 as the hepatic receptor for the hormone asprosin and placed it upstream of cAMP signaling in glucose metabolism.\",\n      \"evidence\": \"Review synthesizing genetic and biochemical studies of the asprosin-OR4M1 interaction and cAMP activation in liver\",\n      \"pmids\": [\"32198197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis, not primary data in this entry\", \"Direct binding stoichiometry and receptor coupling not detailed\", \"Tissue specificity of expression not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended asprosin-OR4M1 signaling readouts beyond cAMP by detecting ERK1/2 phosphorylation in a non-hepatic cancer cell line.\",\n      \"evidence\": \"Western blot for ERK1/2 phosphorylation in SKOV-3 ovarian cancer cells treated with 100 nM asprosin, plus RNA sequencing\",\n      \"pmids\": [\"36233808\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"OR4M1 identity as the receptor mediating the ERK effect not directly confirmed\", \"Single cell line\", \"Link between ERK signaling and hepatic phenotype unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Liver-specific Olfr734 knockdown in diet-induced obese mice with glucose metabolism and MASLD assays, corroborated by human T2DM liver biopsy data\",\n      \"pmids\": [\"40806011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown rather than complete knockout\", \"Single lab\", \"Mechanistic link between lipid accumulation and asprosin/cAMP signaling not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the asprosin-OR4M1 signal to the cAMP/PKA/gluconeogenic-enzyme axis by pharmacologically blocking the binding site and tracing the downstream effectors.\",\n      \"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\",\n      \"pmids\": [\"39821628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical characterization of direct asprosin binding\", \"Relationship between cAMP and ERK/JNK branches unestablished\", \"Endogenous neuronal ligand unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ASPROSIN\", \"FBN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}