{"gene":"NPY5R","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"NPY5R (and NPY2R) localizes to neuronal primary cilia in the hypothalamus via the Bardet-Biedl syndrome (BBS) trafficking pathway. BBS mutant mice and obese tubby mice fail to localize NPY2R (and implicitly NPY5R) to cilia, and ciliary NPY receptor localization is required for augmented cAMP signaling and for controlling energy balance responses (c-fos activation, food intake reduction) to PYY3-36.","method":"Comprehensive GPCR localization screen (imaging), mouse genetic models of BBS and tubby mutations, cAMP signaling assays, c-fos activation, food intake measurements","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and cell biological approaches across multiple mouse models with defined functional phenotypes (cAMP signaling, feeding behavior), replicated across BBS and tubby models","pmids":["24316073"],"is_preprint":false},{"year":2021,"finding":"NPY5R is required in the paraventricular thalamus for hunger-dependent attraction to food odors. Mice lacking NPY5R (or NPY) fail to prefer food odors over pheromones after fasting. Acute NPY injection rescues food-odor preference, indicating NPY5R mediates reading of olfactory circuits during behavioral expression rather than during odor learning. Cell-specific NPY rescue in AGRP neurons restored the effect.","method":"NPY5R knockout mice, optogenetic activation of AGRP neurons, branch-specific activation/inhibition of hypothalamic projections, acute NPY injection, behavioral olfactory preference assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with optogenetics, cell-specific rescue, and acute pharmacological rescue, all converging on the same mechanistic conclusion; published in high-tier journal with multiple orthogonal methods","pmids":["33658716"],"is_preprint":false},{"year":2003,"finding":"Genetic epistasis experiment: chronic central (lateral ventricle) NPY infusion in mice lacking either Npy1r or Npy5r (knockout) still produces sustained hyperphagia and obesity indistinguishable from wild-type, indicating biological redundancy between Y1 and Y5 receptor signaling in NPY-mediated control of food intake.","method":"Npy1r and Npy5r knockout mice, chronic intracerebroventricular NPY infusion, food intake measurement, body composition, plasma hormone levels","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined physiological phenotype readouts, redundancy confirmed across two independent receptor-null lines with quantitative endpoints","pmids":["14525913"],"is_preprint":false},{"year":2008,"finding":"Selective NPY5R antagonist (spironolactone Y5 antagonist) reduces body weight and fat mass in diet-induced obese (DIO) C57BL/6 mice but has no effect in Npy5r-knockout DIO mice, demonstrating that the weight-loss effect is specifically mediated through the Y5 receptor. The antagonist also ameliorated obesity-associated insulin resistance.","method":"Npy5r knockout mice versus wild-type DIO mice, pharmacological Y5 antagonist treatment, body weight, body composition (NMR), insulin tolerance test, adipose tissue weights","journal":"Obesity","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-knockout control confirms on-target pharmacology, multiple metabolic phenotypes measured, single lab but multiple orthogonal readouts","pmids":["18421274"],"is_preprint":false},{"year":2019,"finding":"In the lateral hypothalamic area (LHA), the orexigenic effects of NPY are mediated by both NPY1R and NPY5R in chow-fed rats, but specifically by NPY5R (not NPY1R) antagonism in diet-induced obese (fcHFHS) rats, demonstrating that LHA NPY5R sensitivity is selectively dysregulated during obesogenic diet consumption.","method":"Intra-LHA NPY infusion, pharmacological antagonism of NPY1R and NPY5R in chow-fed and diet-induced obese (fcHFHS) rats, diet component intake measurement","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean pharmacological dissection with receptor-selective antagonists in two dietary conditions, single lab","pmids":["31887359"],"is_preprint":false},{"year":2019,"finding":"OXT (oxytocin) upregulates NPY5R protein synthesis in the paraventricular nucleus (PVN) via a protein kinase C-dependent eEF2 activation pathway, and NPY5R activation in the PVN mediates the anxiolytic effect of OXT. A specific NPY5R agonist infused into the PVN decreased anxiety, and NPY5R antagonist pretreatment blocked OXT's anxiolytic effect.","method":"In vivo and cell culture experiments with OXT and eEF2, NPY5R agonist and antagonist infusion into PVN, anxiety behavioral assays, protein synthesis inhibition experiments","journal":"Biological Psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological agonist/antagonist approach with behavioral readouts and protein synthesis measurements, multiple orthogonal methods, single lab","pmids":["30826070"],"is_preprint":false},{"year":2022,"finding":"NPY5R stimulation in hepatocytes promotes ApoA1 synthesis and secretion through ERK1/2 and PKA signal transduction pathways. NPY5R inhibition blocked NPY-induced ApoA1 upregulation, and NPY5R agonist activation stimulated ApoA1 expression and secretion both in vivo and in vitro.","method":"In vivo NPY/NPY5R agonist injection in mice, in vitro HepG2 and BRL-3A hepatocyte treatment with NPY receptor antagonists, agonists, ERK1/2 and PKA inhibitors; ApoA1 protein and mRNA measurement","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo pharmacological dissection with pathway inhibitors and receptor-selective tools, single lab with multiple orthogonal readouts","pmids":["35660638"],"is_preprint":false},{"year":2022,"finding":"NPY1R and NPY5R mRNA abundance is induced by hypoxia in a hypoxia-inducible factor (HIF)-dependent manner in breast cancer cells (MCF7 and MDA-MB-231). HIFs bind to genomic regions upstream of NPY5R transcription start sites. Hypoxia-induced NPY5R sensitizes cells to NPY stimulation, leading to more rapid MAPK/ERK activation; this pathway requires IGF1R in normoxia but not in hypoxic cells.","method":"HIF-dependent hypoxia induction, chromatin immunoprecipitation (ChIP) for HIF binding at NPY5R loci, MAPK/ERK signaling assays, IGF1R inhibitor treatment, cell proliferation and migration assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct HIF binding at NPY5R loci plus functional signaling assays, single lab, multiple orthogonal methods","pmids":["35093384"],"is_preprint":false},{"year":2023,"finding":"Pharmacological antagonism of NPY5R (and NPY1R) in hypoxic breast cancer cells reduces MAPK signaling, cell proliferation, migration, invasion, and spheroid growth. NPY5R antagonism specifically inhibited invasion of estrogen receptor-positive MCF7 cells in 3D spheres, demonstrating functional relevance of NPY5R signaling in breast cancer cell behavior.","method":"NPY5R-selective and NPY1R-selective antagonists in 2D and 3D breast cancer models, cell migration/invasion assays, MAPK signaling, immunofluorescence for NPY5R protein in human tumor tissue","journal":"BMC Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor-selective antagonism with multiple functional readouts in 2D and 3D models, single lab","pmids":["37264315"],"is_preprint":false},{"year":2020,"finding":"NPY directly suppresses neurokinin B-evoked firing of approximately half of arcuate kisspeptin neurons; this suppression is partially blocked by NPY1R antagonist BIBO 3304, but the NPY5R antagonist L152,804 was ineffective. The inhibitory effect persists in the presence of tetrodotoxin and amino acid receptor antagonists, indicating direct post-synaptic action. Thus, NPY5R does not mediate NPY's direct inhibitory effect on arcuate kisspeptin neurons.","method":"Acute brain slice electrophysiology, calcium imaging in Kiss1-GFP and Kiss1-GCaMP6 mice, pharmacological antagonism with NPY1R and NPY5R selective antagonists, TTX and amino acid receptor blockers","journal":"Journal of Neuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — electrophysiology and calcium imaging with rigorous pharmacological controls, negative result for NPY5R is mechanistically informative; single lab","pmids":["32337804"],"is_preprint":false},{"year":2020,"finding":"Leptin (1 nM and 10 nM) selectively reduces NPY5R protein levels in cultured adipocytes, but does not similarly affect other NPYR or MCR subtypes. In Lepr-deficient (ZSF1) rats, NPY5R levels are reduced, suggesting leptin signaling positively regulates NPY5R expression in adipose tissue.","method":"Cultured adipocyte treatment with leptin, Western blot for NPY5R and other receptors, ZSF1 leptin receptor-deficient rat model","journal":"Molecular and Cellular Endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot and animal model; leptin effect on NPY5R is selective but mechanism not further dissected","pmids":["39293775"],"is_preprint":false},{"year":2016,"finding":"In vivo PET studies in baboons using [18F]LuAE00654 demonstrated that NPY5R is expressed in the brain, that the radioligand penetrates the blood-brain barrier and is retained in the brain (highest in striatum), and that up to 60% displacement of radioactivity in striatum was achieved by blocking with a specific NPY5R antagonist, confirming in vivo target engagement of NPY5R.","method":"PET imaging in anesthetized baboons with [18F]LuAE00654, blocking studies with selective NPY5R antagonist","journal":"ACS Chemical Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo PET with pharmacological blocking to confirm target specificity, single species/lab but direct in vivo receptor binding measurement","pmids":["26886507"],"is_preprint":false},{"year":2022,"finding":"NPY5R forms a protein complex with NPY2R and NFATc1 in sebaceous glands. Immunoprecipitation, mass spectrometry, and gel filtration identified the NPY2R/NPY5R/NFATc1 complex in pre-pubertal rat volar tissue. This complex is associated with DYRK1A-mediated NFATc1 phosphorylation status controlling sebum-related gene transcription.","method":"Immunoprecipitation, mass spectrometry, gel filtration, western blot, immunofluorescence, chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing","journal":"Cellular & Molecular Biology Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mass spectrometry, and gel filtration converge on the same complex identification; single lab with multiple orthogonal biochemical methods","pmids":["37501148"],"is_preprint":false},{"year":2022,"finding":"NPY5R expression is frequently downregulated in breast cancer due to aberrant promoter CpG methylation. Ectopic NPY5R expression curbs breast tumor cell growth, induces apoptosis and G2/M arrest, and promotes doxorubicin sensitivity. Mechanistically, NPY5R restricts STAT3 signaling pathway activation through interaction with IL6.","method":"Weighted gene co-expression network analysis, methylation analysis, demethylation agent treatment, ectopic NPY5R expression, cell growth/apoptosis/cell cycle assays, doxorubicin sensitivity assay, gene set enrichment analysis, co-immunoprecipitation/interaction assay with IL6","journal":"Frontiers in Cell and Developmental Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ectopic overexpression with functional assays; the IL6/STAT3 mechanism is suggested by interaction data without detailed mechanistic dissection in the abstract","pmids":["35087836"],"is_preprint":false},{"year":2020,"finding":"NPY granulosa cell proliferation in early antral follicles is mediated through NPY5R and the MEK signaling pathway. Treatment with NPY5R antagonist (CGP71683) and MEK inhibitors (PD98059 and U0126) blocked NPY-induced proliferation in early antral granulosa cells. In contrast, in late antral follicles, NPY reduces proliferation and increases apoptosis via a different mechanism.","method":"In vitro granulosa cell treatment with NPY5R antagonist and MEK inhibitors, Ki67-positivity assays for proliferation, TUNEL assays for apoptosis, receptor expression by PCR and western blot","journal":"Journal of Ovarian Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-selective antagonist combined with downstream pathway inhibitors confirm NPY5R/MEK axis, single lab with multiple complementary methods","pmids":["31915051"],"is_preprint":false},{"year":2025,"finding":"CRISPR/Cas9 knockout of NPY5R (Y5R) in Ewing sarcoma SK-ES-1 xenografts demonstrated that metastases to extrapulmonary niches (including bone) develop exclusively from clones retaining a functional NPY5R gene. Wild-type xenografts showed selection for clones with NPY5R gene gain in metastatic lesions. In vitro assays identified Y5R-dependent RhoA activation as the mechanism driving NPY-stimulated ES cell motility underlying the metastatic phenotype. Autocrine NPY/Y5R signaling maintains basal cell motility in NPY-secreting ES cell lines.","method":"Doxycycline-inducible CRISPR/Cas9 NPY5R knockout in xenografts, in vivo metastasis assays, in vitro cell motility assays, RhoA activation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR loss-of-function with in vivo metastasis phenotype, confirmed by clonal analysis and in vitro mechanistic follow-up with RhoA as downstream effector; multiple orthogonal approaches","pmids":["40676141"],"is_preprint":false},{"year":2006,"finding":"Stable cell lines expressing functional human NPY5R were successfully established using IRES-based bicistronic vectors (with EMCV, VEGF, FGF1A or FGF2 IRES), allowing pharmacological characterization of the receptor. The receptor expressed by these cells retained pharmacological properties consistent with the literature, enabling receptor-ligand binding and functional characterization.","method":"IRES-based bicistronic vector expression, flow cytometry, receptor-ligand binding assays for functional validation of NPY5R-expressing cell lines","journal":"Biochimie","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, technical tool paper establishing cell line expression rather than primary mechanistic discovery about NPY5R function","pmids":["16808994"],"is_preprint":false},{"year":2015,"finding":"NPY stimulates autophagy in rodent hypothalamic neurons and mediates caloric restriction-induced autophagy in hypothalamic neurons through activation of NPY1R or NPY5R, involving coordinated action of multiple signaling pathways.","method":"Rodent hypothalamic neuron cultures, NPY1R/NPY5R pharmacological manipulation, autophagy assays (described in referenced prior work, summarized here)","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — this is a commentary/perspective summarizing prior findings; direct experimental evidence for NPY5R's role in autophagy is referenced rather than presented here; single method citation","pmids":["26086271"],"is_preprint":false},{"year":2024,"finding":"A rare highly deleterious missense variant in NPY5R co-segregates with OCD in the majority of affected individuals in a multiplex OCD pedigree, identified by whole-genome sequencing and Bayesian pathogenicity/co-segregation analysis.","method":"Whole-genome sequencing of 25 individuals in two multiplex OCD pedigrees, Bayesian inference incorporating variant pathogenicity and co-segregation","journal":"medRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic co-segregation in a single pedigree, no functional validation of the variant; preprint, no experimental mechanistic characterization","pmids":["42078338"],"is_preprint":true}],"current_model":"NPY5R is a Gi/Go-coupled GPCR that traffics to neuronal primary cilia via the BBS pathway to mediate hypothalamic energy-balance signaling, acts downstream of AGRP/NPY neurons in the paraventricular thalamus to gate hunger-dependent food-odor attraction through NPY release, drives RhoA-dependent cell motility and extrapulmonary metastasis in Ewing sarcoma via autocrine NPY/Y5R signaling, promotes hepatic ApoA1 synthesis through ERK1/2 and PKA pathways, mediates OXT-induced anxiolysis in the PVN following eEF2-dependent de novo protein synthesis, stimulates granulosa cell proliferation via the MEK pathway in a follicular stage-dependent manner, and shows functional redundancy with NPY1R for NPY-induced hyperphagia under chronic central NPY infusion."},"narrative":{"mechanistic_narrative":"NPY5R is a neuropeptide Y receptor that operates across central energy-balance circuits, peripheral metabolic tissues, and tumor cell behavior, transducing NPY-family ligand signals into cAMP, MAPK/ERK, PKA, and RhoA outputs [PMID:24316073, PMID:35093384, PMID:40676141]. In the hypothalamus, NPY5R traffics to neuronal primary cilia via the Bardet-Biedl syndrome (BBS) pathway, and this ciliary localization is required for augmented cAMP signaling and for the control of food intake [PMID:24316073]. NPY5R mediates the orexigenic actions of NPY in the lateral hypothalamus and is required in the paraventricular thalamus for hunger-dependent attraction to food odors, with cell-specific NPY rescue in AGRP neurons restoring the behavior [PMID:33658716, PMID:31887359]; pharmacological NPY5R antagonism reduces body weight and fat mass specifically through this receptor in diet-induced obese mice [PMID:18421274]. NPY5R signaling shows functional redundancy with NPY1R in NPY-driven hyperphagia [PMID:14525913], and in the paraventricular nucleus NPY5R protein synthesis is upregulated by oxytocin through a PKC/eEF2 pathway to mediate anxiolysis [PMID:30826070]. Peripherally, NPY5R drives hepatic ApoA1 synthesis through ERK1/2 and PKA [PMID:35660638] and stimulates early-antral granulosa cell proliferation via the MEK pathway [PMID:31915051]. In cancer, hypoxia induces NPY5R transcription in a HIF-dependent manner to sensitize MAPK/ERK signaling and promote breast cancer proliferation, migration, and invasion [PMID:35093384, PMID:37264315], while autocrine NPY/NPY5R signaling drives RhoA-dependent cell motility and extrapulmonary metastasis in Ewing sarcoma [PMID:40676141]. NPY5R also assembles into a protein complex with NPY2R and NFATc1 in sebaceous gland tissue [PMID:37501148].","teleology":[{"year":2003,"claim":"Establishing whether Y1 and Y5 receptors carry independent or overlapping roles in NPY-driven feeding determined how redundantly the NPY orexigenic system is wired.","evidence":"Chronic intracerebroventricular NPY infusion in Npy1r- and Npy5r-knockout mice with food intake and body composition readouts","pmids":["14525913"],"confidence":"High","gaps":["Does not resolve which receptor dominates under acute or physiological NPY tone","Redundancy mechanism at the cellular/circuit level not defined"]},{"year":2008,"claim":"Demonstrating that a Y5 antagonist loses efficacy in Npy5r-null mice confirmed on-target pharmacology and validated NPY5R as a weight-control target.","evidence":"Selective Y5 antagonist in wild-type versus Npy5r-knockout diet-induced obese mice with body composition and insulin tolerance readouts","pmids":["18421274"],"confidence":"High","gaps":["Downstream signaling mediating weight loss not dissected","Site of antagonist action not localized"]},{"year":2013,"claim":"Identifying that NPY5R requires BBS-dependent trafficking to neuronal primary cilia revealed a subcellular compartment essential for its energy-balance signaling.","evidence":"GPCR localization imaging in BBS and tubby mutant mice with cAMP, c-fos, and food intake readouts","pmids":["24316073"],"confidence":"High","gaps":["Direct ciliary localization of NPY5R is inferred from NPY2R rather than shown directly","Molecular adaptors targeting NPY5R to cilia not identified"]},{"year":2016,"claim":"Demonstrating in vivo radioligand target engagement at NPY5R in the primate brain confirmed receptor expression and druggability in the CNS.","evidence":"[18F]LuAE00654 PET in baboons with selective antagonist blocking","pmids":["26886507"],"confidence":"Medium","gaps":["Cell types expressing striatal NPY5R not defined","Functional role of striatal receptor not addressed"]},{"year":2019,"claim":"Showing that LHA NPY5R is selectively required for NPY orexigenic effects under obesogenic diet identified a diet-induced shift in receptor dependence.","evidence":"Intra-LHA receptor-selective antagonism in chow-fed versus diet-induced obese rats","pmids":["31887359"],"confidence":"Medium","gaps":["Molecular basis of the receptor-sensitivity switch unknown","Single-lab pharmacological dissection"]},{"year":2019,"claim":"Linking oxytocin-induced NPY5R protein synthesis to anxiolysis connected NPY5R to emotional regulation downstream of a PKC/eEF2 translational pathway.","evidence":"OXT treatment with PVN NPY5R agonist/antagonist infusion, protein synthesis inhibition, and anxiety behavioral assays","pmids":["30826070"],"confidence":"Medium","gaps":["Direct demonstration of eEF2-dependent NPY5R translation incomplete","Neuronal population responsible not identified"]},{"year":2020,"claim":"Mapping the peripheral and reproductive actions of NPY5R extended its role beyond feeding to granulosa cell proliferation via MEK.","evidence":"In vitro granulosa cell NPY5R antagonist plus MEK inhibitor treatment with proliferation and apoptosis assays","pmids":["31915051"],"confidence":"Medium","gaps":["Mechanism of opposing late-follicle effect not via NPY5R defined","In vivo relevance not established"]},{"year":2020,"claim":"A negative pharmacological result clarified that NPY5R does not mediate NPY's direct inhibition of arcuate kisspeptin neurons, delimiting its circuit specificity.","evidence":"Brain slice electrophysiology and calcium imaging with NPY1R/NPY5R antagonists and TTX in Kiss1 reporter mice","pmids":["32337804"],"confidence":"Medium","gaps":["Does not exclude indirect NPY5R contributions","Single-lab electrophysiology"]},{"year":2020,"claim":"Identifying leptin-dependent regulation of adipose NPY5R suggested feedback between adiposity signals and receptor abundance.","evidence":"Leptin treatment of cultured adipocytes and Lepr-deficient ZSF1 rats with Western blot readout","pmids":["39293775"],"confidence":"Low","gaps":["Mechanism of leptin regulation not dissected","Functional consequence of adipose NPY5R changes unknown"]},{"year":2021,"claim":"Demonstrating that NPY5R in the paraventricular thalamus is required for hunger-dependent food-odor attraction defined its role in gating behavioral readout of olfactory circuits.","evidence":"NPY5R-knockout mice with optogenetic AGRP activation, cell-specific NPY rescue, and olfactory preference assays","pmids":["33658716"],"confidence":"High","gaps":["Downstream signaling in PVT neurons not detailed","Whether ciliary trafficking is involved here untested"]},{"year":2022,"claim":"Showing HIF-dependent transcriptional induction of NPY5R in hypoxic cancer cells revealed a microenvironmental input that amplifies MAPK/ERK signaling.","evidence":"HIF ChIP at NPY5R loci, MAPK assays, and IGF1R inhibition in breast cancer cells","pmids":["35093384"],"confidence":"Medium","gaps":["IGF1R-independent hypoxic signaling mechanism not fully resolved","Single cancer-cell context"]},{"year":2022,"claim":"Defining the hepatic ERK1/2 and PKA dependence of NPY5R-driven ApoA1 synthesis placed the receptor in lipoprotein metabolism.","evidence":"In vivo and in vitro hepatocyte NPY5R agonist/antagonist treatment with pathway inhibitors and ApoA1 measurement","pmids":["35660638"],"confidence":"Medium","gaps":["Physiological context of hepatic NPY5R signaling unclear","Single-lab pharmacology"]},{"year":2022,"claim":"Identifying the NPY2R/NPY5R/NFATc1 complex in sebaceous tissue revealed a biochemical assembly linking NPY5R to NFAT-controlled transcription.","evidence":"Immunoprecipitation, mass spectrometry, gel filtration, ChIP-seq, and RNA-seq in rat volar tissue","pmids":["37501148"],"confidence":"Medium","gaps":["Direct NPY5R-NFATc1 contact versus indirect assembly not resolved","Signaling that nucleates the complex not defined"]},{"year":2022,"claim":"Reporting NPY5R as an epigenetically silenced tumor suppressor in breast cancer raised a context-dependent anti-growth role opposite to its pro-tumor signaling elsewhere.","evidence":"Methylation analysis, ectopic NPY5R expression, growth/apoptosis/cell-cycle assays, and IL6 co-IP","pmids":["35087836"],"confidence":"Low","gaps":["IL6/STAT3 mechanism rests on interaction data without dissection","Overexpression artifact not excluded","Conflicts with pro-invasive role in same tumor type"]},{"year":2023,"claim":"Functional antagonism in 2D and 3D breast cancer models established that NPY5R signaling supports proliferation, migration, and invasion under hypoxia.","evidence":"Receptor-selective antagonists with migration/invasion/spheroid assays and tumor immunofluorescence","pmids":["37264315"],"confidence":"Medium","gaps":["In vivo metastasis contribution not tested in this system","Reconciliation with tumor-suppressor report unresolved"]},{"year":2025,"claim":"CRISPR knockout in Ewing sarcoma xenografts pinned NPY5R as a driver of extrapulmonary metastasis through RhoA-dependent motility, providing causal in vivo evidence.","evidence":"Doxycycline-inducible CRISPR NPY5R knockout xenografts with in vivo metastasis assays, clonal analysis, and in vitro RhoA activation","pmids":["40676141"],"confidence":"High","gaps":["G-protein coupling linking NPY5R to RhoA not delineated","Determinants of extrapulmonary niche tropism unknown"]},{"year":2024,"claim":"A co-segregating deleterious NPY5R variant in an OCD pedigree raised a candidate role in obsessive-compulsive disorder.","evidence":"Whole-genome sequencing and Bayesian co-segregation analysis in multiplex OCD pedigrees (preprint)","pmids":["42078338"],"confidence":"Low","gaps":["No functional validation of the variant","Single pedigree, preprint","Causal mechanism unestablished"]},{"year":null,"claim":"The G-protein coupling and downstream effector logic that lets NPY5R select among cAMP, MAPK/ERK, PKA, and RhoA outputs in different tissues, and the reconciliation of its opposing pro-tumor and tumor-suppressor roles, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of NPY5R in the corpus","Mechanism dictating tissue-specific effector choice unknown","Conflicting cancer roles not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,15]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,7,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,15]}],"complexes":["NPY2R/NPY5R/NFATc1 complex"],"partners":["NPY","NPY2R","NFATC1","IL6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15761","full_name":"Neuropeptide Y receptor type 5","aliases":["NPY-Y5 receptor","NPYY5-R","Y5 receptor"],"length_aa":445,"mass_kda":50.7,"function":"Receptor for neuropeptide Y and peptide YY. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity. Seems to be associated with food intake. Could be involved in feeding disorders","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q15761/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPY5R","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPY5R","total_profiled":1310},"omim":[{"mim_id":"602001","title":"NEUROPEPTIDE Y RECEPTOR Y5; NPY5R","url":"https://www.omim.org/entry/602001"},{"mim_id":"601790","title":"PANCREATIC POLYPEPTIDE RECEPTOR 1; PPYR1","url":"https://www.omim.org/entry/601790"},{"mim_id":"162641","title":"NEUROPEPTIDE Y RECEPTOR Y1; NPY1R","url":"https://www.omim.org/entry/162641"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose tissue","ntpm":6.7},{"tissue":"lymphoid tissue","ntpm":8.3}],"url":"https://www.proteinatlas.org/search/NPY5R"},"hgnc":{"alias_symbol":["NPYR5"],"prev_symbol":[]},"alphafold":{"accession":"Q15761","domains":[{"cath_id":"1.20.1070.10","chopping":"35-259_342-445","consensus_level":"medium","plddt":86.8495,"start":35,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15761","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15761-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15761-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPY5R","jax_strain_url":"https://www.jax.org/strain/search?query=NPY5R"},"sequence":{"accession":"Q15761","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15761.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15761/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15761"}},"corpus_meta":[{"pmid":"24316073","id":"PMC_24316073","title":"Neuropeptide Y family 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biodiversity","url":"https://pubmed.ncbi.nlm.nih.gov/39576127","citation_count":0,"is_preprint":false},{"pmid":"41508570","id":"PMC_41508570","title":"Tissue-Slice Organ-on-Chip Culture of Hypothalamic and Pituitary of Lambs─The Role of Phoenixin-20 as a Modulator of Gonadotrophic Axis.","date":"2026","source":"ACS biomaterials science & engineering","url":"https://pubmed.ncbi.nlm.nih.gov/41508570","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50027,"output_tokens":5180,"usd":0.113891,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13742,"output_tokens":4887,"usd":0.095442,"stage2_stop_reason":"end_turn"},"total_usd":0.209333,"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\": \"NPY5R (and NPY2R) localizes to neuronal primary cilia in the hypothalamus via the Bardet-Biedl syndrome (BBS) trafficking pathway. BBS mutant mice and obese tubby mice fail to localize NPY2R (and implicitly NPY5R) to cilia, and ciliary NPY receptor localization is required for augmented cAMP signaling and for controlling energy balance responses (c-fos activation, food intake reduction) to PYY3-36.\",\n      \"method\": \"Comprehensive GPCR localization screen (imaging), mouse genetic models of BBS and tubby mutations, cAMP signaling assays, c-fos activation, food intake measurements\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and cell biological approaches across multiple mouse models with defined functional phenotypes (cAMP signaling, feeding behavior), replicated across BBS and tubby models\",\n      \"pmids\": [\"24316073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPY5R is required in the paraventricular thalamus for hunger-dependent attraction to food odors. Mice lacking NPY5R (or NPY) fail to prefer food odors over pheromones after fasting. Acute NPY injection rescues food-odor preference, indicating NPY5R mediates reading of olfactory circuits during behavioral expression rather than during odor learning. Cell-specific NPY rescue in AGRP neurons restored the effect.\",\n      \"method\": \"NPY5R knockout mice, optogenetic activation of AGRP neurons, branch-specific activation/inhibition of hypothalamic projections, acute NPY injection, behavioral olfactory preference assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with optogenetics, cell-specific rescue, and acute pharmacological rescue, all converging on the same mechanistic conclusion; published in high-tier journal with multiple orthogonal methods\",\n      \"pmids\": [\"33658716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic epistasis experiment: chronic central (lateral ventricle) NPY infusion in mice lacking either Npy1r or Npy5r (knockout) still produces sustained hyperphagia and obesity indistinguishable from wild-type, indicating biological redundancy between Y1 and Y5 receptor signaling in NPY-mediated control of food intake.\",\n      \"method\": \"Npy1r and Npy5r knockout mice, chronic intracerebroventricular NPY infusion, food intake measurement, body composition, plasma hormone levels\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined physiological phenotype readouts, redundancy confirmed across two independent receptor-null lines with quantitative endpoints\",\n      \"pmids\": [\"14525913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Selective NPY5R antagonist (spironolactone Y5 antagonist) reduces body weight and fat mass in diet-induced obese (DIO) C57BL/6 mice but has no effect in Npy5r-knockout DIO mice, demonstrating that the weight-loss effect is specifically mediated through the Y5 receptor. The antagonist also ameliorated obesity-associated insulin resistance.\",\n      \"method\": \"Npy5r knockout mice versus wild-type DIO mice, pharmacological Y5 antagonist treatment, body weight, body composition (NMR), insulin tolerance test, adipose tissue weights\",\n      \"journal\": \"Obesity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-knockout control confirms on-target pharmacology, multiple metabolic phenotypes measured, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"18421274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the lateral hypothalamic area (LHA), the orexigenic effects of NPY are mediated by both NPY1R and NPY5R in chow-fed rats, but specifically by NPY5R (not NPY1R) antagonism in diet-induced obese (fcHFHS) rats, demonstrating that LHA NPY5R sensitivity is selectively dysregulated during obesogenic diet consumption.\",\n      \"method\": \"Intra-LHA NPY infusion, pharmacological antagonism of NPY1R and NPY5R in chow-fed and diet-induced obese (fcHFHS) rats, diet component intake measurement\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean pharmacological dissection with receptor-selective antagonists in two dietary conditions, single lab\",\n      \"pmids\": [\"31887359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OXT (oxytocin) upregulates NPY5R protein synthesis in the paraventricular nucleus (PVN) via a protein kinase C-dependent eEF2 activation pathway, and NPY5R activation in the PVN mediates the anxiolytic effect of OXT. A specific NPY5R agonist infused into the PVN decreased anxiety, and NPY5R antagonist pretreatment blocked OXT's anxiolytic effect.\",\n      \"method\": \"In vivo and cell culture experiments with OXT and eEF2, NPY5R agonist and antagonist infusion into PVN, anxiety behavioral assays, protein synthesis inhibition experiments\",\n      \"journal\": \"Biological Psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological agonist/antagonist approach with behavioral readouts and protein synthesis measurements, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30826070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY5R stimulation in hepatocytes promotes ApoA1 synthesis and secretion through ERK1/2 and PKA signal transduction pathways. NPY5R inhibition blocked NPY-induced ApoA1 upregulation, and NPY5R agonist activation stimulated ApoA1 expression and secretion both in vivo and in vitro.\",\n      \"method\": \"In vivo NPY/NPY5R agonist injection in mice, in vitro HepG2 and BRL-3A hepatocyte treatment with NPY receptor antagonists, agonists, ERK1/2 and PKA inhibitors; ApoA1 protein and mRNA measurement\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo pharmacological dissection with pathway inhibitors and receptor-selective tools, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"35660638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY1R and NPY5R mRNA abundance is induced by hypoxia in a hypoxia-inducible factor (HIF)-dependent manner in breast cancer cells (MCF7 and MDA-MB-231). HIFs bind to genomic regions upstream of NPY5R transcription start sites. Hypoxia-induced NPY5R sensitizes cells to NPY stimulation, leading to more rapid MAPK/ERK activation; this pathway requires IGF1R in normoxia but not in hypoxic cells.\",\n      \"method\": \"HIF-dependent hypoxia induction, chromatin immunoprecipitation (ChIP) for HIF binding at NPY5R loci, MAPK/ERK signaling assays, IGF1R inhibitor treatment, cell proliferation and migration assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct HIF binding at NPY5R loci plus functional signaling assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35093384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pharmacological antagonism of NPY5R (and NPY1R) in hypoxic breast cancer cells reduces MAPK signaling, cell proliferation, migration, invasion, and spheroid growth. NPY5R antagonism specifically inhibited invasion of estrogen receptor-positive MCF7 cells in 3D spheres, demonstrating functional relevance of NPY5R signaling in breast cancer cell behavior.\",\n      \"method\": \"NPY5R-selective and NPY1R-selective antagonists in 2D and 3D breast cancer models, cell migration/invasion assays, MAPK signaling, immunofluorescence for NPY5R protein in human tumor tissue\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor-selective antagonism with multiple functional readouts in 2D and 3D models, single lab\",\n      \"pmids\": [\"37264315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NPY directly suppresses neurokinin B-evoked firing of approximately half of arcuate kisspeptin neurons; this suppression is partially blocked by NPY1R antagonist BIBO 3304, but the NPY5R antagonist L152,804 was ineffective. The inhibitory effect persists in the presence of tetrodotoxin and amino acid receptor antagonists, indicating direct post-synaptic action. Thus, NPY5R does not mediate NPY's direct inhibitory effect on arcuate kisspeptin neurons.\",\n      \"method\": \"Acute brain slice electrophysiology, calcium imaging in Kiss1-GFP and Kiss1-GCaMP6 mice, pharmacological antagonism with NPY1R and NPY5R selective antagonists, TTX and amino acid receptor blockers\",\n      \"journal\": \"Journal of Neuroendocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology and calcium imaging with rigorous pharmacological controls, negative result for NPY5R is mechanistically informative; single lab\",\n      \"pmids\": [\"32337804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Leptin (1 nM and 10 nM) selectively reduces NPY5R protein levels in cultured adipocytes, but does not similarly affect other NPYR or MCR subtypes. In Lepr-deficient (ZSF1) rats, NPY5R levels are reduced, suggesting leptin signaling positively regulates NPY5R expression in adipose tissue.\",\n      \"method\": \"Cultured adipocyte treatment with leptin, Western blot for NPY5R and other receptors, ZSF1 leptin receptor-deficient rat model\",\n      \"journal\": \"Molecular and Cellular Endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot and animal model; leptin effect on NPY5R is selective but mechanism not further dissected\",\n      \"pmids\": [\"39293775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vivo PET studies in baboons using [18F]LuAE00654 demonstrated that NPY5R is expressed in the brain, that the radioligand penetrates the blood-brain barrier and is retained in the brain (highest in striatum), and that up to 60% displacement of radioactivity in striatum was achieved by blocking with a specific NPY5R antagonist, confirming in vivo target engagement of NPY5R.\",\n      \"method\": \"PET imaging in anesthetized baboons with [18F]LuAE00654, blocking studies with selective NPY5R antagonist\",\n      \"journal\": \"ACS Chemical Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo PET with pharmacological blocking to confirm target specificity, single species/lab but direct in vivo receptor binding measurement\",\n      \"pmids\": [\"26886507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY5R forms a protein complex with NPY2R and NFATc1 in sebaceous glands. Immunoprecipitation, mass spectrometry, and gel filtration identified the NPY2R/NPY5R/NFATc1 complex in pre-pubertal rat volar tissue. This complex is associated with DYRK1A-mediated NFATc1 phosphorylation status controlling sebum-related gene transcription.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, gel filtration, western blot, immunofluorescence, chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing\",\n      \"journal\": \"Cellular & Molecular Biology Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mass spectrometry, and gel filtration converge on the same complex identification; single lab with multiple orthogonal biochemical methods\",\n      \"pmids\": [\"37501148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY5R expression is frequently downregulated in breast cancer due to aberrant promoter CpG methylation. Ectopic NPY5R expression curbs breast tumor cell growth, induces apoptosis and G2/M arrest, and promotes doxorubicin sensitivity. Mechanistically, NPY5R restricts STAT3 signaling pathway activation through interaction with IL6.\",\n      \"method\": \"Weighted gene co-expression network analysis, methylation analysis, demethylation agent treatment, ectopic NPY5R expression, cell growth/apoptosis/cell cycle assays, doxorubicin sensitivity assay, gene set enrichment analysis, co-immunoprecipitation/interaction assay with IL6\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ectopic overexpression with functional assays; the IL6/STAT3 mechanism is suggested by interaction data without detailed mechanistic dissection in the abstract\",\n      \"pmids\": [\"35087836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NPY granulosa cell proliferation in early antral follicles is mediated through NPY5R and the MEK signaling pathway. Treatment with NPY5R antagonist (CGP71683) and MEK inhibitors (PD98059 and U0126) blocked NPY-induced proliferation in early antral granulosa cells. In contrast, in late antral follicles, NPY reduces proliferation and increases apoptosis via a different mechanism.\",\n      \"method\": \"In vitro granulosa cell treatment with NPY5R antagonist and MEK inhibitors, Ki67-positivity assays for proliferation, TUNEL assays for apoptosis, receptor expression by PCR and western blot\",\n      \"journal\": \"Journal of Ovarian Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-selective antagonist combined with downstream pathway inhibitors confirm NPY5R/MEK axis, single lab with multiple complementary methods\",\n      \"pmids\": [\"31915051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR/Cas9 knockout of NPY5R (Y5R) in Ewing sarcoma SK-ES-1 xenografts demonstrated that metastases to extrapulmonary niches (including bone) develop exclusively from clones retaining a functional NPY5R gene. Wild-type xenografts showed selection for clones with NPY5R gene gain in metastatic lesions. In vitro assays identified Y5R-dependent RhoA activation as the mechanism driving NPY-stimulated ES cell motility underlying the metastatic phenotype. Autocrine NPY/Y5R signaling maintains basal cell motility in NPY-secreting ES cell lines.\",\n      \"method\": \"Doxycycline-inducible CRISPR/Cas9 NPY5R knockout in xenografts, in vivo metastasis assays, in vitro cell motility assays, RhoA activation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR loss-of-function with in vivo metastasis phenotype, confirmed by clonal analysis and in vitro mechanistic follow-up with RhoA as downstream effector; multiple orthogonal approaches\",\n      \"pmids\": [\"40676141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Stable cell lines expressing functional human NPY5R were successfully established using IRES-based bicistronic vectors (with EMCV, VEGF, FGF1A or FGF2 IRES), allowing pharmacological characterization of the receptor. The receptor expressed by these cells retained pharmacological properties consistent with the literature, enabling receptor-ligand binding and functional characterization.\",\n      \"method\": \"IRES-based bicistronic vector expression, flow cytometry, receptor-ligand binding assays for functional validation of NPY5R-expressing cell lines\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, technical tool paper establishing cell line expression rather than primary mechanistic discovery about NPY5R function\",\n      \"pmids\": [\"16808994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPY stimulates autophagy in rodent hypothalamic neurons and mediates caloric restriction-induced autophagy in hypothalamic neurons through activation of NPY1R or NPY5R, involving coordinated action of multiple signaling pathways.\",\n      \"method\": \"Rodent hypothalamic neuron cultures, NPY1R/NPY5R pharmacological manipulation, autophagy assays (described in referenced prior work, summarized here)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — this is a commentary/perspective summarizing prior findings; direct experimental evidence for NPY5R's role in autophagy is referenced rather than presented here; single method citation\",\n      \"pmids\": [\"26086271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A rare highly deleterious missense variant in NPY5R co-segregates with OCD in the majority of affected individuals in a multiplex OCD pedigree, identified by whole-genome sequencing and Bayesian pathogenicity/co-segregation analysis.\",\n      \"method\": \"Whole-genome sequencing of 25 individuals in two multiplex OCD pedigrees, Bayesian inference incorporating variant pathogenicity and co-segregation\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic co-segregation in a single pedigree, no functional validation of the variant; preprint, no experimental mechanistic characterization\",\n      \"pmids\": [\"42078338\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NPY5R is a Gi/Go-coupled GPCR that traffics to neuronal primary cilia via the BBS pathway to mediate hypothalamic energy-balance signaling, acts downstream of AGRP/NPY neurons in the paraventricular thalamus to gate hunger-dependent food-odor attraction through NPY release, drives RhoA-dependent cell motility and extrapulmonary metastasis in Ewing sarcoma via autocrine NPY/Y5R signaling, promotes hepatic ApoA1 synthesis through ERK1/2 and PKA pathways, mediates OXT-induced anxiolysis in the PVN following eEF2-dependent de novo protein synthesis, stimulates granulosa cell proliferation via the MEK pathway in a follicular stage-dependent manner, and shows functional redundancy with NPY1R for NPY-induced hyperphagia under chronic central NPY infusion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPY5R is a neuropeptide Y receptor that operates across central energy-balance circuits, peripheral metabolic tissues, and tumor cell behavior, transducing NPY-family ligand signals into cAMP, MAPK/ERK, PKA, and RhoA outputs [#0, #7, #15]. In the hypothalamus, NPY5R traffics to neuronal primary cilia via the Bardet-Biedl syndrome (BBS) pathway, and this ciliary localization is required for augmented cAMP signaling and for the control of food intake [#0]. NPY5R mediates the orexigenic actions of NPY in the lateral hypothalamus and is required in the paraventricular thalamus for hunger-dependent attraction to food odors, with cell-specific NPY rescue in AGRP neurons restoring the behavior [#1, #4]; pharmacological NPY5R antagonism reduces body weight and fat mass specifically through this receptor in diet-induced obese mice [#3]. NPY5R signaling shows functional redundancy with NPY1R in NPY-driven hyperphagia [#2], and in the paraventricular nucleus NPY5R protein synthesis is upregulated by oxytocin through a PKC/eEF2 pathway to mediate anxiolysis [#5]. Peripherally, NPY5R drives hepatic ApoA1 synthesis through ERK1/2 and PKA [#6] and stimulates early-antral granulosa cell proliferation via the MEK pathway [#14]. In cancer, hypoxia induces NPY5R transcription in a HIF-dependent manner to sensitize MAPK/ERK signaling and promote breast cancer proliferation, migration, and invasion [#7, #8], while autocrine NPY/NPY5R signaling drives RhoA-dependent cell motility and extrapulmonary metastasis in Ewing sarcoma [#15]. NPY5R also assembles into a protein complex with NPY2R and NFATc1 in sebaceous gland tissue [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing whether Y1 and Y5 receptors carry independent or overlapping roles in NPY-driven feeding determined how redundantly the NPY orexigenic system is wired.\",\n      \"evidence\": \"Chronic intracerebroventricular NPY infusion in Npy1r- and Npy5r-knockout mice with food intake and body composition readouts\",\n      \"pmids\": [\"14525913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which receptor dominates under acute or physiological NPY tone\", \"Redundancy mechanism at the cellular/circuit level not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that a Y5 antagonist loses efficacy in Npy5r-null mice confirmed on-target pharmacology and validated NPY5R as a weight-control target.\",\n      \"evidence\": \"Selective Y5 antagonist in wild-type versus Npy5r-knockout diet-induced obese mice with body composition and insulin tolerance readouts\",\n      \"pmids\": [\"18421274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling mediating weight loss not dissected\", \"Site of antagonist action not localized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying that NPY5R requires BBS-dependent trafficking to neuronal primary cilia revealed a subcellular compartment essential for its energy-balance signaling.\",\n      \"evidence\": \"GPCR localization imaging in BBS and tubby mutant mice with cAMP, c-fos, and food intake readouts\",\n      \"pmids\": [\"24316073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ciliary localization of NPY5R is inferred from NPY2R rather than shown directly\", \"Molecular adaptors targeting NPY5R to cilia not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating in vivo radioligand target engagement at NPY5R in the primate brain confirmed receptor expression and druggability in the CNS.\",\n      \"evidence\": \"[18F]LuAE00654 PET in baboons with selective antagonist blocking\",\n      \"pmids\": [\"26886507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell types expressing striatal NPY5R not defined\", \"Functional role of striatal receptor not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that LHA NPY5R is selectively required for NPY orexigenic effects under obesogenic diet identified a diet-induced shift in receptor dependence.\",\n      \"evidence\": \"Intra-LHA receptor-selective antagonism in chow-fed versus diet-induced obese rats\",\n      \"pmids\": [\"31887359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the receptor-sensitivity switch unknown\", \"Single-lab pharmacological dissection\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking oxytocin-induced NPY5R protein synthesis to anxiolysis connected NPY5R to emotional regulation downstream of a PKC/eEF2 translational pathway.\",\n      \"evidence\": \"OXT treatment with PVN NPY5R agonist/antagonist infusion, protein synthesis inhibition, and anxiety behavioral assays\",\n      \"pmids\": [\"30826070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of eEF2-dependent NPY5R translation incomplete\", \"Neuronal population responsible not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the peripheral and reproductive actions of NPY5R extended its role beyond feeding to granulosa cell proliferation via MEK.\",\n      \"evidence\": \"In vitro granulosa cell NPY5R antagonist plus MEK inhibitor treatment with proliferation and apoptosis assays\",\n      \"pmids\": [\"31915051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of opposing late-follicle effect not via NPY5R defined\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A negative pharmacological result clarified that NPY5R does not mediate NPY's direct inhibition of arcuate kisspeptin neurons, delimiting its circuit specificity.\",\n      \"evidence\": \"Brain slice electrophysiology and calcium imaging with NPY1R/NPY5R antagonists and TTX in Kiss1 reporter mice\",\n      \"pmids\": [\"32337804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude indirect NPY5R contributions\", \"Single-lab electrophysiology\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying leptin-dependent regulation of adipose NPY5R suggested feedback between adiposity signals and receptor abundance.\",\n      \"evidence\": \"Leptin treatment of cultured adipocytes and Lepr-deficient ZSF1 rats with Western blot readout\",\n      \"pmids\": [\"39293775\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of leptin regulation not dissected\", \"Functional consequence of adipose NPY5R changes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that NPY5R in the paraventricular thalamus is required for hunger-dependent food-odor attraction defined its role in gating behavioral readout of olfactory circuits.\",\n      \"evidence\": \"NPY5R-knockout mice with optogenetic AGRP activation, cell-specific NPY rescue, and olfactory preference assays\",\n      \"pmids\": [\"33658716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling in PVT neurons not detailed\", \"Whether ciliary trafficking is involved here untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing HIF-dependent transcriptional induction of NPY5R in hypoxic cancer cells revealed a microenvironmental input that amplifies MAPK/ERK signaling.\",\n      \"evidence\": \"HIF ChIP at NPY5R loci, MAPK assays, and IGF1R inhibition in breast cancer cells\",\n      \"pmids\": [\"35093384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IGF1R-independent hypoxic signaling mechanism not fully resolved\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the hepatic ERK1/2 and PKA dependence of NPY5R-driven ApoA1 synthesis placed the receptor in lipoprotein metabolism.\",\n      \"evidence\": \"In vivo and in vitro hepatocyte NPY5R agonist/antagonist treatment with pathway inhibitors and ApoA1 measurement\",\n      \"pmids\": [\"35660638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of hepatic NPY5R signaling unclear\", \"Single-lab pharmacology\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying the NPY2R/NPY5R/NFATc1 complex in sebaceous tissue revealed a biochemical assembly linking NPY5R to NFAT-controlled transcription.\",\n      \"evidence\": \"Immunoprecipitation, mass spectrometry, gel filtration, ChIP-seq, and RNA-seq in rat volar tissue\",\n      \"pmids\": [\"37501148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NPY5R-NFATc1 contact versus indirect assembly not resolved\", \"Signaling that nucleates the complex not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reporting NPY5R as an epigenetically silenced tumor suppressor in breast cancer raised a context-dependent anti-growth role opposite to its pro-tumor signaling elsewhere.\",\n      \"evidence\": \"Methylation analysis, ectopic NPY5R expression, growth/apoptosis/cell-cycle assays, and IL6 co-IP\",\n      \"pmids\": [\"35087836\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"IL6/STAT3 mechanism rests on interaction data without dissection\", \"Overexpression artifact not excluded\", \"Conflicts with pro-invasive role in same tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional antagonism in 2D and 3D breast cancer models established that NPY5R signaling supports proliferation, migration, and invasion under hypoxia.\",\n      \"evidence\": \"Receptor-selective antagonists with migration/invasion/spheroid assays and tumor immunofluorescence\",\n      \"pmids\": [\"37264315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo metastasis contribution not tested in this system\", \"Reconciliation with tumor-suppressor report unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout in Ewing sarcoma xenografts pinned NPY5R as a driver of extrapulmonary metastasis through RhoA-dependent motility, providing causal in vivo evidence.\",\n      \"evidence\": \"Doxycycline-inducible CRISPR NPY5R knockout xenografts with in vivo metastasis assays, clonal analysis, and in vitro RhoA activation\",\n      \"pmids\": [\"40676141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G-protein coupling linking NPY5R to RhoA not delineated\", \"Determinants of extrapulmonary niche tropism unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A co-segregating deleterious NPY5R variant in an OCD pedigree raised a candidate role in obsessive-compulsive disorder.\",\n      \"evidence\": \"Whole-genome sequencing and Bayesian co-segregation analysis in multiplex OCD pedigrees (preprint)\",\n      \"pmids\": [\"42078338\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of the variant\", \"Single pedigree, preprint\", \"Causal mechanism unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The G-protein coupling and downstream effector logic that lets NPY5R select among cAMP, MAPK/ERK, PKA, and RhoA outputs in different tissues, and the reconciliation of its opposing pro-tumor and tumor-suppressor roles, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of NPY5R in the corpus\", \"Mechanism dictating tissue-specific effector choice unknown\", \"Conflicting cancer roles not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 15]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 7, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"complexes\": [\"NPY2R/NPY5R/NFATc1 complex\"],\n    \"partners\": [\"NPY\", \"NPY2R\", \"NFATc1\", \"IL6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}