{"gene":"FAM237B","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2020,"finding":"FAM237B activates GPR83, a G-protein-coupled receptor, after posttranslational processing (C-terminal cleavage and amidation) in endocrine host cells, albeit with reduced potency compared to the paralog FAM237A.","method":"Functional GPCR screening in stable endocrine host cell lines expressing preprohormones; posttranslational processing demonstrated by expression system competent for regulated secretory pathway","journal":"SLAS discovery : advancing life sciences R & D","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell-based assay with processing characterization, single lab, moderate mechanistic detail","pmids":["32713278"],"is_preprint":false},{"year":2023,"finding":"Mature human FAM237B at nanomolar concentrations (1–10 nM) significantly activates GPR83 as measured by β-arrestin recruitment, establishing it as an endogenous agonist for GPR83.","method":"In vitro peptide preparation via intein-fusion approach; NanoBiT-based β-arrestin recruitment assay","journal":"Amino acids","confidence":"High","confidence_rationale":"Tier 1–2 — recombinant protein reconstitution with quantitative functional assay; replicates and extends prior finding","pmids":["37689599"],"is_preprint":false},{"year":2025,"finding":"IGF1 regulates Fam237b expression in hypothalamic neurons, producing an overall anorexigenic expression profile alongside Agrp, Npy, Pomc, and other neuropeptides.","method":"RT-qPCR and single-cell RNA sequencing in mouse and human hypothalamic neuron models treated with IGF1","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 — transcriptomic and qPCR evidence in defined cell models, single lab","pmids":["40105689"],"is_preprint":false},{"year":2026,"finding":"FAM237B expression is enriched in arcuate NPY/AgRP neurons, rises with fasting or serum withdrawal, and is suppressed by insulin via PI3K (but not MEK) signaling, paralleling Agrp regulation.","method":"Single-cell and bulk RNA sequencing; RT-qPCR in NPY/AgRP hypothalamic cell models; pharmacological inhibition of PI3K and MEK pathways; in vivo fasting experiments in mice","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (scRNA-seq, qPCR, pathway inhibitors, in vivo), pathway placement established by epistasis-like pharmacological dissection","pmids":["41765162"],"is_preprint":false},{"year":2026,"finding":"Pro-inflammatory stimuli (LPS, IL-6, TNF-α) robustly increase Fam237b mRNA in primary hypothalamic cultures and NPY/AgRP cell models, linking neuroinflammation to FAM237B regulation.","method":"Treatment of primary hypothalamic cultures and NPY/AgRP cell models with LPS, IL-6, and TNF-α; RT-qPCR measurement of Fam237b mRNA","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple inflammatory stimuli tested in two cell systems, single lab","pmids":["41765162"],"is_preprint":false},{"year":2026,"finding":"FAM237B (Gm8773/NPGM) is a 139 amino acid microprotein with a conserved C-terminal region consistent with prohormone processing, evolutionarily conserved from jawless vertebrates to mammals, and likely predates AgRP.","method":"Comparative genomics and synteny analysis across vertebrate species","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 — computational/comparative genomics plus sequence analysis, supported by functional context in the same study","pmids":["41765162"],"is_preprint":false}],"current_model":"FAM237B is an evolutionarily conserved hypothalamic microprotein/neuropeptide enriched in arcuate NPY/AgRP neurons that, after prohormone processing (C-terminal cleavage and amidation), acts as an endogenous agonist for the GPCR GPR83 at nanomolar concentrations via β-arrestin recruitment; its expression is upregulated by fasting and pro-inflammatory stimuli, and suppressed by insulin through PI3K signaling, positioning it as a metabolically and inflammatorily regulated orexigenic signal in energy homeostasis."},"narrative":{"teleology":[{"year":2020,"claim":"The first functional assignment for FAM237B established that, after prohormone processing in endocrine cells, the gene product activates the orphan receptor GPR83, identifying a ligand–receptor pairing for an uncharacterized microprotein.","evidence":"Functional GPCR screening in stable endocrine host cell lines competent for regulated secretory-pathway processing","pmids":["32713278"],"confidence":"Medium","gaps":["Single-lab observation not yet replicated by an independent group","Potency and signaling pathway downstream of GPR83 not quantified","In vivo relevance of FAM237B–GPR83 axis not tested"]},{"year":2023,"claim":"Quantitative reconstitution with recombinant mature FAM237B confirmed nanomolar agonist activity at GPR83 via β-arrestin recruitment, establishing the signaling modality and solidifying the ligand–receptor relationship.","evidence":"Intein-fusion recombinant peptide preparation; NanoBiT-based β-arrestin recruitment assay","pmids":["37689599"],"confidence":"High","gaps":["G-protein coupling profile (Gi/Gq/Gs) not determined","No structure–activity relationship for processed C-terminal peptide","Physiological downstream signaling consequences of GPR83 activation by FAM237B remain undefined"]},{"year":2025,"claim":"Demonstration that IGF1 regulates Fam237b expression in hypothalamic neurons placed the gene within a growth-factor-responsive transcriptional network alongside canonical energy-balance neuropeptides (Agrp, Npy, Pomc).","evidence":"RT-qPCR and single-cell RNA sequencing in mouse and human hypothalamic neuron models treated with IGF1","pmids":["40105689"],"confidence":"Medium","gaps":["Direction and magnitude of IGF1 effect on Fam237b specifically not fully dissected from co-regulated genes","Signaling pathway mediating IGF1 regulation of Fam237b not identified","Single-lab finding"]},{"year":2026,"claim":"A comprehensive study resolved the cellular identity, metabolic regulation, inflammatory responsiveness, and evolutionary origin of FAM237B: the gene is enriched in arcuate NPY/AgRP neurons, induced by fasting and inflammatory cytokines, suppressed by insulin via PI3K, and conserved from jawless vertebrates, predating AgRP itself.","evidence":"scRNA-seq, bulk RNA-seq, RT-qPCR in NPY/AgRP cell models and primary hypothalamic cultures; PI3K/MEK pharmacological inhibitors; in vivo fasting in mice; comparative genomics and synteny analysis","pmids":["41765162"],"confidence":"High","gaps":["No loss-of-function (knockout/knockdown) data demonstrating requirement for FAM237B in energy homeostasis","Whether FAM237B acts in an autocrine, paracrine, or endocrine manner via GPR83 in the hypothalamus is unknown","Prohormone processing enzymes and secretion dynamics have not been characterized"]},{"year":null,"claim":"It remains unknown whether FAM237B is required for normal energy balance in vivo, what downstream signaling cascades GPR83 activation by FAM237B engages in hypothalamic circuits, and whether FAM237B contributes to metabolic disease phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic loss-of-function or gain-of-function studies in animal models","GPR83 downstream effector cascade in NPY/AgRP neurons uncharacterized","No human genetic association data linking FAM237B variants to metabolic or inflammatory disease"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]}],"complexes":[],"partners":["GPR83"],"other_free_text":[]},"mechanistic_narrative":"FAM237B is a hypothalamic microprotein/neuropeptide precursor enriched in arcuate NPY/AgRP neurons that functions as an endogenous agonist of the G-protein-coupled receptor GPR83. After posttranslational processing involving C-terminal cleavage and amidation, mature FAM237B activates GPR83 at nanomolar concentrations via β-arrestin recruitment [PMID:32713278, PMID:37689599]. FAM237B expression is upregulated by fasting and pro-inflammatory stimuli (LPS, IL-6, TNF-α) and suppressed by insulin through PI3K signaling, paralleling AgRP regulation and positioning it as a metabolically and inflammatorily regulated orexigenic neuropeptide [PMID:41765162]. The gene encodes a 139-amino-acid prohormone with a conserved C-terminal domain present from jawless vertebrates to mammals, predating AgRP in evolutionary origin [PMID:41765162]."},"prefetch_data":{"uniprot":{"accession":"A0A1B0GVD1","full_name":"Protein FAM237B","aliases":[],"length_aa":139,"mass_kda":16.3,"function":"May be capable of activating GPR83 via the GNAQ signaling pathway","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/A0A1B0GVD1/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM237B"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM237B","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM237B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"A0A1B0GVD1","domains":[{"cath_id":"-","chopping":"45-139","consensus_level":"high","plddt":77.0905,"start":45,"end":139},{"cath_id":"1.20.5","chopping":"2-43","consensus_level":"medium","plddt":70.2462,"start":2,"end":43}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A1B0GVD1","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0A1B0GVD1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0A1B0GVD1-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM237B","jax_strain_url":"https://www.jax.org/strain/search?query=FAM237B"},"sequence":{"accession":"A0A1B0GVD1","fasta_url":"https://rest.uniprot.org/uniprotkb/A0A1B0GVD1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0A1B0GVD1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A1B0GVD1"}},"corpus_meta":[{"pmid":"32713278","id":"PMC_32713278","title":"A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands.","date":"2020","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/32713278","citation_count":9,"is_preprint":false},{"pmid":"38483771","id":"PMC_38483771","title":"Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes.","date":"2024","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38483771","citation_count":8,"is_preprint":false},{"pmid":"37689599","id":"PMC_37689599","title":"Nanomolar range of FAM237B can activate receptor GPR83.","date":"2023","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/37689599","citation_count":3,"is_preprint":false},{"pmid":"40105689","id":"PMC_40105689","title":"IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological Conditions.","date":"2025","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40105689","citation_count":3,"is_preprint":false},{"pmid":"41765162","id":"PMC_41765162","title":"FAM237B, a conserved orexigenic neuropeptide, is regulated by fasting, insulin, and neuroinflammation in mouse hypothalamic NPY/AgRP neurons.","date":"2026","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/41765162","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3692,"output_tokens":1340,"usd":0.015588},"stage2":{"model":"claude-opus-4-6","input_tokens":4603,"output_tokens":1433,"usd":0.08826},"total_usd":0.103848,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM237B activates GPR83, a G-protein-coupled receptor, after posttranslational processing (C-terminal cleavage and amidation) in endocrine host cells, albeit with reduced potency compared to the paralog FAM237A.\",\n      \"method\": \"Functional GPCR screening in stable endocrine host cell lines expressing preprohormones; posttranslational processing demonstrated by expression system competent for regulated secretory pathway\",\n      \"journal\": \"SLAS discovery : advancing life sciences R & D\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assay with processing characterization, single lab, moderate mechanistic detail\",\n      \"pmids\": [\"32713278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mature human FAM237B at nanomolar concentrations (1–10 nM) significantly activates GPR83 as measured by β-arrestin recruitment, establishing it as an endogenous agonist for GPR83.\",\n      \"method\": \"In vitro peptide preparation via intein-fusion approach; NanoBiT-based β-arrestin recruitment assay\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — recombinant protein reconstitution with quantitative functional assay; replicates and extends prior finding\",\n      \"pmids\": [\"37689599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF1 regulates Fam237b expression in hypothalamic neurons, producing an overall anorexigenic expression profile alongside Agrp, Npy, Pomc, and other neuropeptides.\",\n      \"method\": \"RT-qPCR and single-cell RNA sequencing in mouse and human hypothalamic neuron models treated with IGF1\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — transcriptomic and qPCR evidence in defined cell models, single lab\",\n      \"pmids\": [\"40105689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM237B expression is enriched in arcuate NPY/AgRP neurons, rises with fasting or serum withdrawal, and is suppressed by insulin via PI3K (but not MEK) signaling, paralleling Agrp regulation.\",\n      \"method\": \"Single-cell and bulk RNA sequencing; RT-qPCR in NPY/AgRP hypothalamic cell models; pharmacological inhibition of PI3K and MEK pathways; in vivo fasting experiments in mice\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (scRNA-seq, qPCR, pathway inhibitors, in vivo), pathway placement established by epistasis-like pharmacological dissection\",\n      \"pmids\": [\"41765162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Pro-inflammatory stimuli (LPS, IL-6, TNF-α) robustly increase Fam237b mRNA in primary hypothalamic cultures and NPY/AgRP cell models, linking neuroinflammation to FAM237B regulation.\",\n      \"method\": \"Treatment of primary hypothalamic cultures and NPY/AgRP cell models with LPS, IL-6, and TNF-α; RT-qPCR measurement of Fam237b mRNA\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple inflammatory stimuli tested in two cell systems, single lab\",\n      \"pmids\": [\"41765162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM237B (Gm8773/NPGM) is a 139 amino acid microprotein with a conserved C-terminal region consistent with prohormone processing, evolutionarily conserved from jawless vertebrates to mammals, and likely predates AgRP.\",\n      \"method\": \"Comparative genomics and synteny analysis across vertebrate species\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — computational/comparative genomics plus sequence analysis, supported by functional context in the same study\",\n      \"pmids\": [\"41765162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM237B is an evolutionarily conserved hypothalamic microprotein/neuropeptide enriched in arcuate NPY/AgRP neurons that, after prohormone processing (C-terminal cleavage and amidation), acts as an endogenous agonist for the GPCR GPR83 at nanomolar concentrations via β-arrestin recruitment; its expression is upregulated by fasting and pro-inflammatory stimuli, and suppressed by insulin through PI3K signaling, positioning it as a metabolically and inflammatorily regulated orexigenic signal in energy homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FAM237B is a hypothalamic microprotein/neuropeptide precursor enriched in arcuate NPY/AgRP neurons that functions as an endogenous agonist of the G-protein-coupled receptor GPR83. After posttranslational processing involving C-terminal cleavage and amidation, mature FAM237B activates GPR83 at nanomolar concentrations via β-arrestin recruitment [PMID:32713278, PMID:37689599]. FAM237B expression is upregulated by fasting and pro-inflammatory stimuli (LPS, IL-6, TNF-α) and suppressed by insulin through PI3K signaling, paralleling AgRP regulation and positioning it as a metabolically and inflammatorily regulated orexigenic neuropeptide [PMID:41765162]. The gene encodes a 139-amino-acid prohormone with a conserved C-terminal domain present from jawless vertebrates to mammals, predating AgRP in evolutionary origin [PMID:41765162].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"The first functional assignment for FAM237B established that, after prohormone processing in endocrine cells, the gene product activates the orphan receptor GPR83, identifying a ligand–receptor pairing for an uncharacterized microprotein.\",\n      \"evidence\": \"Functional GPCR screening in stable endocrine host cell lines competent for regulated secretory-pathway processing\",\n      \"pmids\": [\"32713278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab observation not yet replicated by an independent group\",\n        \"Potency and signaling pathway downstream of GPR83 not quantified\",\n        \"In vivo relevance of FAM237B–GPR83 axis not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantitative reconstitution with recombinant mature FAM237B confirmed nanomolar agonist activity at GPR83 via β-arrestin recruitment, establishing the signaling modality and solidifying the ligand–receptor relationship.\",\n      \"evidence\": \"Intein-fusion recombinant peptide preparation; NanoBiT-based β-arrestin recruitment assay\",\n      \"pmids\": [\"37689599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"G-protein coupling profile (Gi/Gq/Gs) not determined\",\n        \"No structure–activity relationship for processed C-terminal peptide\",\n        \"Physiological downstream signaling consequences of GPR83 activation by FAM237B remain undefined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that IGF1 regulates Fam237b expression in hypothalamic neurons placed the gene within a growth-factor-responsive transcriptional network alongside canonical energy-balance neuropeptides (Agrp, Npy, Pomc).\",\n      \"evidence\": \"RT-qPCR and single-cell RNA sequencing in mouse and human hypothalamic neuron models treated with IGF1\",\n      \"pmids\": [\"40105689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direction and magnitude of IGF1 effect on Fam237b specifically not fully dissected from co-regulated genes\",\n        \"Signaling pathway mediating IGF1 regulation of Fam237b not identified\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A comprehensive study resolved the cellular identity, metabolic regulation, inflammatory responsiveness, and evolutionary origin of FAM237B: the gene is enriched in arcuate NPY/AgRP neurons, induced by fasting and inflammatory cytokines, suppressed by insulin via PI3K, and conserved from jawless vertebrates, predating AgRP itself.\",\n      \"evidence\": \"scRNA-seq, bulk RNA-seq, RT-qPCR in NPY/AgRP cell models and primary hypothalamic cultures; PI3K/MEK pharmacological inhibitors; in vivo fasting in mice; comparative genomics and synteny analysis\",\n      \"pmids\": [\"41765162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No loss-of-function (knockout/knockdown) data demonstrating requirement for FAM237B in energy homeostasis\",\n        \"Whether FAM237B acts in an autocrine, paracrine, or endocrine manner via GPR83 in the hypothalamus is unknown\",\n        \"Prohormone processing enzymes and secretion dynamics have not been characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether FAM237B is required for normal energy balance in vivo, what downstream signaling cascades GPR83 activation by FAM237B engages in hypothalamic circuits, and whether FAM237B contributes to metabolic disease phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic loss-of-function or gain-of-function studies in animal models\",\n        \"GPR83 downstream effector cascade in NPY/AgRP neurons uncharacterized\",\n        \"No human genetic association data linking FAM237B variants to metabolic or inflammatory disease\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GPR83\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}