FAM237B

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).

1. 2020 Medium

   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

   PMID:32713278

   Open questions at the time

   • 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
2. 2023 High

   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

   PMID:37689599

   Open questions at the time

   • 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
3. 2025 Medium

   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

   PMID:40105689

   Open questions at the time

   • 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
4. 2026 High

   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

   PMID:41765162

   Open questions at the time

   • 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

• 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.
• 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