{"gene":"NPY","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2022,"finding":"Cryo-EM/X-ray structures of human Y1, Y2, and Y4 receptors in complex with NPY or pancreatic polypeptide and Gi1 protein reveal distinct binding poses of the peptide ligand across receptor subtypes; the N-terminus of NPY forms extensive interactions with Y1 but not Y2 or Y4 receptors. A conserved aspartate in the third extracellular loop is essential for ligand binding in all four Y receptors but engages different arginine residues on the ligand depending on receptor subtype. Mutagenesis and functional studies confirmed subtype-specific receptor–peptide interactions.","method":"Cryo-EM/X-ray crystallography, receptor mutagenesis, functional assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structures combined with mutagenesis and functional validation in one rigorous study","pmids":["35507650"],"is_preprint":false},{"year":2015,"finding":"NPY Y1 receptor (Y1R) activation in the bed nucleus of the stria terminalis (BNST) suppresses binge alcohol drinking by enhancing inhibitory synaptic transmission specifically onto CRF neurons via a Gi-mediated, PKA-dependent postsynaptic mechanism. Chronic alcohol drinking leads to persistent alterations in Y1R function in this circuit in both mice and monkeys.","method":"Whole-cell patch-clamp electrophysiology, pharmacological receptor agonist/antagonist application, chemogenetics (DREADD), convergent physiological and behavioral assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (electrophysiology, chemogenetics, pharmacology) in a single study, replicated across two mammalian species","pmids":["25751534"],"is_preprint":false},{"year":2019,"finding":"NPY, but not AgRP or GABA, is uniquely required for the long-lasting (sustained) hunger drive generated by AgRP neuron stimulation. Selective deletion of NPY from AgRP neurons abolished optically-stimulated feeding; re-expression of NPY specifically in AgRP neurons rescued this phenotype.","method":"Conditional knockout (cell-type-specific NPY deletion), optogenetics, re-expression rescue experiment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective genetic deletion plus rescue by re-expression in the same cell type, clear behavioral readout","pmids":["31033437"],"is_preprint":false},{"year":2000,"finding":"NPY potentiates phenylephrine-induced MAPK (ERK, JNK, p38) activation and PKC stimulation in primary neonatal cardiomyocytes via NPY Y5 receptors coupled to Gi protein in a pertussis-toxin-sensitive, calcium-independent manner; this synergism is specific to alpha-adrenergic (phenylephrine) but not angiotensin II stimulation.","method":"Neonatal cardiomyocyte culture, pharmacological agonist/antagonist studies, pertussis toxin treatment, Western blot (MAPK phosphorylation), PKC activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct in vitro mechanistic dissection using pertussis toxin and receptor-selective ligands, multiple signaling readouts","pmids":["10660688"],"is_preprint":false},{"year":1993,"finding":"NPY-2 (Y2) receptor agonist NPY(13-36) and NPY-1 (Y1) agonist [Pro34]-NPY have opposite effects on high-threshold calcium currents in rat nodose ganglion neurons: Y2 activation decreases and Y1 activation increases peak transient high-threshold Ca2+ current amplitude.","method":"Whole-cell patch-clamp electrophysiology with selective receptor agonists","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological measurement with subtype-selective agonists, multiple neurons tested","pmids":["8395583"],"is_preprint":false},{"year":2001,"finding":"NPY produced by human adrenal chromaffin cells locally enhances catecholamine secretion in an autocrine/paracrine manner, likely through the putative y3 receptor; Y1, Y2, Y4, and Y5 receptor mRNAs are expressed and functional (stimulate intracellular calcium rise) on chromaffin cells, but an NPY-immunoneutralizing antibody (not receptor-selective antagonists) markedly attenuated constitutive catecholamine release.","method":"RT-PCR, receptor-selective agonist/antagonist pharmacology, intracellular calcium measurement, immunoneutralization, RIA for catecholamines and NPY","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab; autocrine mechanism established but receptor identity partly uncertain","pmids":["11739470"],"is_preprint":false},{"year":2016,"finding":"NPY promotes intestinal epithelial cell proliferation and suppresses apoptosis through PI3-K/pAkt (β-catenin) signaling and downregulation of miR-375; NPY knockout mice show reduced polyp formation in a DSS-induced colitis-tumorigenesis model.","method":"NPY knockout mouse model (in vivo), intestinal epithelial cell line (T84) in vitro, Western blot, PCNA/Ki67/TUNEL staining, miRNA expression analysis","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo with in vitro mechanistic pathway dissection, single lab","pmids":["27856419"],"is_preprint":false},{"year":2010,"finding":"ATP-induced neuroproliferation in adult mouse olfactory epithelium requires NPY upregulation followed by Y1 receptor activation; intranasal purinergic receptor antagonism blocks NPY upregulation, and Y1 receptor antagonism blocks BrdU incorporation (proliferation).","method":"Intranasal pharmacological interventions, BrdU labeling, protein quantification (Western blot/IHC), purinergic receptor antagonist pre-treatment","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with two receptor blockers defining a signaling sequence, single lab","pmids":["20211262"],"is_preprint":false},{"year":2008,"finding":"NPY elicits an attractive axon turning response in embryonic DRG growth cones and increases growth rate via the NPY Y1 receptor; Y1 receptor is expressed in neuroblasts of the rostral migratory stream; Y1- or Y2-receptor knockout mice have fewer proliferating precursor cells and neuroblasts in the subventricular zone/rostral migratory stream and fewer olfactory bulb neurons.","method":"Growth cone turning assay (live imaging, asymmetric gradient application), knockout mouse analysis, immunohistochemistry","journal":"Nutrition (Burbank, Los Angeles County, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (growth cone turning) plus genetic loss-of-function, single lab","pmids":["18725084"],"is_preprint":false},{"year":2008,"finding":"NPY receptor binding requires a conserved aspartate residue in the third extracellular loop of all four Y receptors; the specific arginine on the NPY ligand that interacts with this aspartate differs depending on receptor subtype. These were determined by receptor mutagenesis, chimeric receptors, and modified peptide synthesis.","method":"Receptor mutagenesis, receptor chimeras, peptide analog synthesis, binding assays","journal":"Nutrition (Burbank, Los Angeles County, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis combined with binding assays, single review-style compilation but grounded in primary experimental data cited therein","pmids":["18725084"],"is_preprint":false},{"year":2000,"finding":"Human adipocytes predominantly express Y1 receptors (high-affinity sites for [125I]PYY and [125I](Leu31,Pro34)PYY with Y1 pharmacological profile) that mediate NPY's antilipolytic effect and stimulate leptin secretion; Y2 receptor expression is absent. Both effects were fully blocked by selective Y1 antagonists SR120819A and BIBP3226.","method":"RT-PCR, radioligand binding assay, [35S]GTPγS binding, lipolysis assay in isolated adipocytes, leptin secretion RIA, receptor antagonists","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays with selective antagonists, single lab","pmids":["10858507"],"is_preprint":false},{"year":1997,"finding":"In the dorsal vagal complex (DVC), Y2 receptor activation suppresses TRH-stimulated gastric motility (mimicking peripheral PYY action), while Y1 receptor activation stimulates gastric motility from basal state; NPY effects depend on the motility state. PYY is rapidly converted to a Y2-selective agonist by DPP-IV (dipeptidyl aminopeptidase IV), explaining its predominant Y2 action in this context.","method":"Microinjection of receptor-selective agonists into DVC, in vivo gastric motility measurement","journal":"Neurogastroenterology and motility","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacological receptor dissection in vivo, single lab","pmids":["9198086"],"is_preprint":false},{"year":1993,"finding":"Microinjection of Y1 receptor agonist [Leu31,Pro34]NPY into the nucleus tractus solitarius (NTS) produces vasodepressor and bradycardic responses; sub-picomolar doses of the Y2 agonist NPY(13-36) into NTS counteract these Y1-mediated vasodepressor responses, indicating a Y2/Y1 receptor-receptor interaction in the NTS.","method":"Stereotaxic microinjection of receptor-selective agonists, in vivo blood pressure and heart rate measurement","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor-selective dissection in vivo, single lab","pmids":["8221064"],"is_preprint":false},{"year":2001,"finding":"NPY, acting through Y1 receptor (postsynaptic), potentiates phenylephrine (alpha1-adrenergic)-induced vasopressin and oxytocin release from hypothalamo-neurohypophysial explants in a sustained manner; Y1 agonist [Leu31,Pro34]-NPY increases VP and OT release but does not potentiate ATP-induced responses, indicating signaling specificity.","method":"Perifusion of hypothalamic-neurohypophysial explants, selective receptor agonists, RIA for vasopressin and oxytocin","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ex vivo pharmacological dissection with multiple agonists and readouts, single lab","pmids":["11124136"],"is_preprint":false},{"year":2015,"finding":"In the central amygdala (CEm), NPY Y2 receptors are located presynaptically (not on NPY neurons themselves) and their activation by Y2 agonist PYY3-36 reduces both inhibitory and excitatory synaptic transmission. Absence of NPY or Y2 receptors leads to increased GABA release specifically at inhibitory synapses in the CEm.","method":"Retrograde tract tracing, immunofluorescence, whole-cell patch-clamp electrophysiology, Y2 receptor knockout mice","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological dissection plus genetic KO, single lab","pmids":["26365505"],"is_preprint":false},{"year":2002,"finding":"NPY antidepressant-like activity in the mouse forced swimming test is mediated by the Y1 receptor subtype: Y1 agonist [Leu31Pro34]PYY mimics NPY's anti-immobility effect, Y1 antagonists (BIBO3304, BIBP3226) block it, while Y2 agonist NPY(13-36) is inactive and Y2 antagonist BIIE0246 also reduces immobility (presumably by potentiating endogenous NPY release).","method":"Intracerebroventricular injection, mouse forced swimming test, receptor-selective agonists and antagonists, open field locomotion control","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with multiple selective ligands, single lab with robust behavioral read-out","pmids":["11927186"],"is_preprint":false},{"year":1999,"finding":"NPY Y5 receptor activation mediates NPY-induced feeding and also contributes to decreases in brown adipose tissue temperature and energy expenditure (reduced oxygen consumption); Y1, Y2, and Y4 receptor agonists did not replicate these effects when given ICV.","method":"ICV injection of receptor-selective agonists, indirect calorimetry, implanted BAT temperature transponders, food intake measurement","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with multiple selective agonists, in vivo metabolic readouts, single lab","pmids":["10564216"],"is_preprint":false},{"year":2016,"finding":"Systemic NPY reduces trigeminocervical complex (TCC) neuronal firing in response to dural nociceptive trigeminovascular activation via the NPY Y1 receptor; Y1 agonist mimics this effect and Y1 antagonist blocks it; Y2 and Y5 receptor agonists are ineffective.","method":"In vivo electrophysiology in anesthetized rats, systemic drug administration, receptor-selective agonists/antagonist","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo electrophysiological receptor dissection, single lab","pmids":["27023421"],"is_preprint":false},{"year":2007,"finding":"NPY Y1 receptor antagonist (1229U91) blocks NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters, whereas Y5 receptor antagonist (CGP71683) does not; Y1 agonist but not Y5 agonist recapitulates the torpor effect, establishing Y1 receptor as necessary and sufficient for NPY-induced torpor.","method":"ICV injection, receptor-selective agonists/antagonists, body temperature telemetry, counterbalanced pharmacological design","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological necessity and sufficiency established with receptor-selective tools, single lab","pmids":["17989140"],"is_preprint":false},{"year":2003,"finding":"NPY suppresses experimental autoimmune encephalomyelitis (EAE) via Y1 receptors: Y1 receptor agonists inhibit EAE induction, a Y1 antagonist causes earlier EAE onset, and ex vivo analysis shows Y1 signaling in autoreactive T cells shifts them toward Th2 and inhibits Th1 responses. Y5 agonist had no protective effect.","method":"EAE induction in C57BL/6 mice, pharmacological receptor agonist/antagonist treatment, ex vivo T cell restimulation, cytokine profiling","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in vivo plus ex vivo cellular mechanism, single lab","pmids":["14500640"],"is_preprint":false},{"year":2021,"finding":"Ascending skeletal interoceptive signaling downregulates hypothalamic NPY expression by inducing SMILE (small heterodimer partner-interacting leucine zipper protein), which binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY transcription. Reduced NPY signaling (via Y1R inhibition) accelerates free fatty acid oxidation in osteoblasts and rescues bone loss.","method":"EP4 sensory nerve knockout mice, hypothalamic molecular analysis, promoter binding (pCREB/SMILE complex), Y1R pharmacological inhibition, bone phenotype analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with molecular mechanistic follow-up identifying transcriptional complex, single lab","pmids":["34468315"],"is_preprint":false},{"year":1985,"finding":"NPY-like immunoreactivity is transported axonally in peripheral sympathetic neurons at a rapid rate (~3 mm/h), as demonstrated by accumulation above sciatic nerve ligations; reserpine depletes NPY from cardiac sympathetic nerve terminals (but not ganglia) in a manner dependent on intact nerve activity, distinguishing NPY storage/release from noradrenaline; 6-OHDA denervation depletes NPY from terminal fields but increases it in ganglia.","method":"Sciatic nerve ligation, reserpine and 6-OHDA pharmacology, radioimmunoassay, immunohistochemistry, HPLC","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct axonal transport measurement by ligation accumulation, multiple tissue pharmacological dissections, single lab","pmids":["2858824"],"is_preprint":false},{"year":1990,"finding":"NPY is co-stored with noradrenaline in large dense-cored vesicles and is released preferentially at high stimulation frequencies or strong sympathetic activation; NPY release is inhibited by prejunctional alpha-2 adrenoceptors and adenosine receptors, and facilitated by angiotensin II or beta-receptor activation. NPY acts prejunctionally to inhibit both NA and NPY release, and postjunctionally to potentiate vasoconstriction. A large amidated C-terminal portion of NPY is necessary for receptor binding, cAMP inhibition, and vasoconstrictor effects.","method":"Sympathetic nerve stimulation (peripheral vascular preparations), pharmacological pre/postjunctional dissection, RIA, cAMP assay, denervation supersensitivity experiments","journal":"Fundamental & clinical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and physiological assays establishing co-transmission mechanism, replicated across multiple vascular beds","pmids":["2170253"],"is_preprint":false},{"year":2008,"finding":"NPY Y2 receptor activation (by NPY(13-36)) provides neuroprotection against AMPA-induced excitotoxicity in hippocampal slice cultures; endogenous NPY via Y1 receptors also contributes to neuroprotection in CA1; AMPA-induced injury increases BDNF in microglia, but this BDNF is not required for the Y2-mediated NPY neuroprotective effect.","method":"Organotypic hippocampal slice culture, AMPA excitotoxicity model, propidium iodide uptake, receptor-selective agonists/antagonists, TrkB-Fc and neutralizing antibody blockade, ELISA, immunohistochemistry","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor dissection in ex vivo model with multiple receptor blockers and pathway controls, single lab","pmids":["18412629"],"is_preprint":false},{"year":2002,"finding":"Y1 receptor immunoreactivity is present in axonal processes of DRG neurons with centrifugal (peripheral) transport demonstrated by accumulation proximal to sciatic nerve crush lesions; Y1R co-localizes with CGRP in peripheral sensory axons and nerve endings near the epidermis.","method":"Immunohistochemistry, nerve crush/ligation lesion experiments, double-labeling (Y1R + CGRP), dorsal rhizotomy","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional lesion paradigm demonstrating axonal transport, single lab","pmids":["11869028"],"is_preprint":false},{"year":2014,"finding":"NPY acting through Y1 receptors induces vasoconstriction and proliferation of pulmonary arterial smooth muscle cells via p38 and PKD pathway activation; selective Y1 antagonist BIBO 3304 blocks both effects; Y1 receptor expression is upregulated in pulmonary hypertension tissue.","method":"Wire myography, calcium imaging, Western blot (p38/PKD phosphorylation), thymidine incorporation proliferation assay, quantitative PCR, selective Y1 antagonist","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct signaling pathway dissection in primary human cells with selective antagonist, single lab","pmids":["24779394"],"is_preprint":false},{"year":2017,"finding":"Insulin signaling specifically in NPY neurons controls food intake, energy expenditure, and GH/IGF-1 axis; selective deletion of the insulin receptor in NPY neurons (in both flies and mice) leads to increased energy stores, obesity, and impaired insulin sensitivity.","method":"Cell-type-specific conditional knockout of insulin receptor in NPY neurons (Drosophila and mouse), metabolic phenotyping","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic deletion with clean metabolic readouts, replicated across two species","pmids":["28580287"],"is_preprint":false}],"current_model":"NPY is a 36-amino-acid neuropeptide that is co-stored with noradrenaline in large dense-cored vesicles of sympathetic neurons and released preferentially at high stimulation frequencies; it signals through four Gi/Go-coupled Y receptors (Y1, Y2, Y4, Y5) whose structures have been resolved in complex with NPY and Gi1 protein, revealing subtype-specific binding poses and a conserved extracellular aspartate essential for ligand engagement. Via Y1 receptors NPY produces anxiolysis, antidepressant-like effects, vasodepressor responses in the NTS, torpor, and suppression of trigeminovascular pain; via Y2 receptors (presynaptically located) it inhibits excitatory and inhibitory synaptic transmission in the amygdala and provides hippocampal neuroprotection; via Y5 receptors it mediates sustained feeding and decreases energy expenditure; NPY Y1R activation in BNST CRF neurons suppresses binge alcohol drinking through a Gi/PKA-dependent postsynaptic mechanism. In the hypothalamus, NPY expression in AgRP neurons uniquely sustains hunger after AgRP neuron activation, and is suppressed by a SMILE–pCREB transcriptional complex downstream of skeletal interoceptive EP4 signaling. Insulin receptor signaling within NPY neurons regulates energy balance, and NPY promotes intestinal epithelial proliferation via PI3-K/β-catenin signaling with miR-375 downregulation."},"narrative":{"mechanistic_narrative":"NPY is a sympathetic and central neuropeptide that couples neuronal activity to feeding, energy balance, autonomic control, and tissue proliferation by acting through a family of Gi/Go-coupled Y receptors [PMID:2170253, PMID:35507650]. In sympathetic neurons NPY is co-stored with noradrenaline in large dense-cored vesicles, transported axonally at rapid rates, and released preferentially during high-frequency or strong sympathetic activation; its amidated C-terminus is required for receptor binding, cAMP inhibition, and vasoconstrictor effects, and it acts both prejunctionally to inhibit transmitter release and postjunctionally to potentiate vasoconstriction [PMID:2858824, PMID:2170253]. Structural and mutagenesis studies define how NPY engages the Y1, Y2, and Y4 receptors with distinct binding poses, with a conserved third-extracellular-loop aspartate essential across all subtypes engaging different ligand arginines depending on receptor subtype [PMID:35507650, PMID:18725084]. Receptor subtype dictates physiology: Y1 signaling mediates antidepressant-like behavior, NTS vasodepressor responses, torpor, suppression of trigeminovascular firing, and suppression of binge alcohol drinking via a Gi/PKA-dependent enhancement of inhibition onto BNST CRF neurons [PMID:11927186, PMID:8221064, PMID:17989140, PMID:27023421, PMID:25751534]; presynaptic Y2 receptors suppress excitatory and inhibitory synaptic transmission in the amygdala and confer hippocampal neuroprotection [PMID:26365505, PMID:18412629]; and Y5 receptors drive feeding and reduced energy expenditure [PMID:10564216]. In the hypothalamus NPY expression in AgRP neurons is uniquely required to sustain hunger after AgRP neuron activation and is transcriptionally repressed by a SMILE–pCREB complex downstream of skeletal interoceptive EP4 signaling, while insulin receptor signaling within NPY neurons governs energy stores and the GH/IGF-1 axis [PMID:31033437, PMID:34468315, PMID:28580287]. Beyond neuronal signaling, NPY promotes epithelial and precursor cell proliferation, driving intestinal epithelial growth via PI3-K/β-catenin signaling with miR-375 downregulation and Y1-dependent neuroproliferation [PMID:27856419, PMID:20211262].","teleology":[{"year":1985,"claim":"Established NPY as an axonally trafficked sympathetic neuropeptide whose storage and depletion behavior is distinct from noradrenaline, raising the question of how it is released.","evidence":"Sciatic nerve ligation, reserpine/6-OHDA pharmacology, RIA and IHC in peripheral sympathetic neurons","pmids":["2858824"],"confidence":"Medium","gaps":["Did not define release kinetics or receptor targets","Vesicular storage with noradrenaline inferred pharmacologically"]},{"year":1990,"claim":"Defined NPY as a sympathetic co-transmitter released at high stimulation frequencies acting pre- and postjunctionally, and identified the amidated C-terminus as the functional binding determinant.","evidence":"Sympathetic nerve stimulation in vascular preparations, pre/postjunctional pharmacology, cAMP assay across multiple vascular beds","pmids":["2170253"],"confidence":"Medium","gaps":["Receptor subtype assignments not yet molecular","Did not resolve atomic basis of receptor engagement"]},{"year":1993,"claim":"Demonstrated that Y1 and Y2 receptors exert opposite effects on the same target, establishing subtype-specific and antagonistic NPY signaling in autonomic circuits.","evidence":"Patch-clamp of nodose ganglion Ca2+ currents with subtype-selective agonists; NTS microinjection with blood pressure/heart rate readouts","pmids":["8395583","8221064"],"confidence":"High","gaps":["Receptor localization (pre- vs postsynaptic) not resolved","Downstream effectors not defined"]},{"year":1997,"claim":"Showed NPY/PYY gastric motility effects are state-dependent and split between Y1 and Y2 receptors, with DPP-IV conversion biasing PYY toward Y2 action.","evidence":"DVC microinjection of receptor-selective agonists with in vivo gastric motility measurement","pmids":["9198086"],"confidence":"Medium","gaps":["Cellular circuit underlying motility state-dependence undefined","No structural basis for ligand selectivity"]},{"year":2000,"claim":"Identified Y5-Gi coupled cross-talk with alpha-adrenergic signaling in cardiomyocytes and Y1-mediated antilipolytic/leptin-stimulating action in adipocytes, extending NPY signaling to peripheral metabolic and cardiac targets.","evidence":"Cardiomyocyte cultures with pertussis toxin and MAPK/PKC readouts; adipocyte radioligand binding, GTPγS, lipolysis and leptin assays with Y1 antagonists","pmids":["10660688","10858507"],"confidence":"High","gaps":["Physiological relevance in vivo not established in these studies","Y5 versus Y1 selectivity tissue-dependent"]},{"year":2001,"claim":"Revealed autocrine/paracrine NPY action enhancing catecholamine secretion in chromaffin cells and Y1-dependent potentiation of vasopressin/oxytocin release, showing NPY amplifies neuroendocrine output.","evidence":"RT-PCR, calcium imaging, immunoneutralization in chromaffin cells; perifused hypothalamo-neurohypophysial explants with selective agonists","pmids":["11739470","11124136"],"confidence":"Medium","gaps":["Putative y3 receptor identity uncertain","Single-lab findings without reciprocal validation"]},{"year":2002,"claim":"Mapped Y1-receptor protein to peripheral sensory axons co-localizing with CGRP and pinned antidepressant-like behavioral effects to the Y1 subtype.","evidence":"IHC with nerve crush/rhizotomy axonal transport paradigm; ICV ligand pharmacology in the forced swimming test","pmids":["11869028","11927186"],"confidence":"Medium","gaps":["Circuit linking sensory Y1R to nociception not defined","Behavioral receptor assignment from pharmacology only"]},{"year":2003,"claim":"Extended NPY signaling to immune regulation, showing Y1 receptors on autoreactive T cells bias toward Th2 and suppress autoimmune neuroinflammation.","evidence":"EAE induction in mice with Y1/Y5 agonist and antagonist treatment, ex vivo T cell restimulation and cytokine profiling","pmids":["14500640"],"confidence":"Medium","gaps":["Direct vs indirect T cell action not fully separated","Single-lab pharmacological epistasis"]},{"year":2007,"claim":"Established Y1 receptor as necessary and sufficient for NPY-induced torpor, separating thermoregulatory control from Y5-mediated feeding.","evidence":"ICV receptor-selective agonist/antagonist with body temperature telemetry in Siberian hamsters","pmids":["17989140"],"confidence":"Medium","gaps":["Effector circuit downstream of Y1R undefined","Species-specific torpor model"]},{"year":2008,"claim":"Defined the conserved aspartate–arginine binding contact for ligand engagement and showed NPY drives neuroprotection and neuroproliferation/axon guidance through Y1 and Y2 receptors.","evidence":"Receptor mutagenesis/chimeras and peptide analogs; growth cone turning assays and Y1/Y2 knockout analysis; hippocampal slice excitotoxicity model with receptor blockers","pmids":["18725084","18412629"],"confidence":"Medium","gaps":["Atomic structure of binding not yet resolved at this stage","Neuroprotective downstream effectors only partly defined"]},{"year":2014,"claim":"Connected Y1 signaling to vascular smooth muscle proliferation and vasoconstriction via p38/PKD, implicating NPY in pulmonary hypertension.","evidence":"Myography, calcium imaging, Western blot and proliferation assays in human pulmonary arterial smooth muscle with selective Y1 antagonist","pmids":["24779394"],"confidence":"Medium","gaps":["Causal role in disease progression in vivo not shown","Single-lab study"]},{"year":2015,"claim":"Localized Y2 receptors presynaptically in the amygdala and defined a Y1-Gi/PKA postsynaptic mechanism onto BNST CRF neurons controlling binge drinking.","evidence":"Patch-clamp electrophysiology, tract tracing, Y2 knockout mice; chemogenetics and pharmacology across mice and monkeys","pmids":["26365505","25751534"],"confidence":"High","gaps":["Long-term circuit remodeling after chronic alcohol incompletely mapped","Y2 presynaptic target neurons partly undefined"]},{"year":2017,"claim":"Showed insulin receptor signaling within NPY neurons is a cell-autonomous regulator of energy stores, obesity, and the GH/IGF-1 axis, conserved across flies and mice.","evidence":"Cell-type-specific insulin receptor knockout in NPY neurons with metabolic phenotyping in Drosophila and mouse","pmids":["28580287"],"confidence":"Medium","gaps":["Downstream transcriptional response in NPY neurons not defined","Link to NPY peptide output not directly measured"]},{"year":2019,"claim":"Demonstrated NPY peptide itself is uniquely required to sustain hunger driven by AgRP neurons, distinguishing it from co-expressed AgRP and GABA.","evidence":"Cell-type-specific NPY deletion plus re-expression rescue with optogenetic feeding readout","pmids":["31033437"],"confidence":"High","gaps":["Receptor subtype mediating sustained hunger not identified here","Temporal dynamics of NPY release undefined"]},{"year":2021,"claim":"Identified the SMILE–pCREB transcriptional complex repressing hypothalamic Npy downstream of skeletal interoceptive EP4 signaling, linking bone-derived signals to NPY-mediated metabolic control.","evidence":"EP4 sensory nerve knockout mice, promoter binding analysis, Y1R inhibition and bone phenotyping","pmids":["34468315"],"confidence":"Medium","gaps":["Direct promoter occupancy detail limited","Single-lab mechanism"]},{"year":2022,"claim":"Resolved atomic-resolution Y1/Y2/Y4–NPY/PP–Gi1 structures, revealing subtype-specific binding poses and confirming the conserved aspartate binding determinant.","evidence":"Cryo-EM/X-ray crystallography with receptor mutagenesis and functional assays","pmids":["35507650"],"confidence":"High","gaps":["Y5 receptor structure not resolved","Conformational basis of biased signaling not addressed"]},{"year":null,"claim":"How NPY release dynamics, receptor subtype switching, and tissue-specific Gi effectors are integrated to produce the divergent feeding, autonomic, behavioral, and proliferative outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking subtype selection to physiological context","Y3/y5 receptor roles incompletely defined","Transcriptional control of NPY across tissues only partly mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,22,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,10,14]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[22,21]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[22,21,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,14,23]}],"complexes":[],"partners":["NPY1R","NPY2R","NPY4R","NPY5R","GNAI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P01303","full_name":"Pro-neuropeptide Y","aliases":[],"length_aa":97,"mass_kda":10.9,"function":"NPY is implicated in the control of feeding and in secretion of gonadotrophin-release hormone","subcellular_location":"Secreted; Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle","url":"https://www.uniprot.org/uniprotkb/P01303/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPY","classification":"Not 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dependence.","date":"2007","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/17239487","citation_count":36,"is_preprint":false},{"pmid":"9802395","id":"PMC_9802395","title":"Is there really an NPY Y3 receptor?","date":"1998","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/9802395","citation_count":36,"is_preprint":false},{"pmid":"8221064","id":"PMC_8221064","title":"Microinjections of subpicomolar amounts of NPY(13-36) into the nucleus tractus solitarius of the rat counteract the vasodepressor responses of NPY(1-36) and of a NPY Y1 receptor agonist.","date":"1993","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8221064","citation_count":36,"is_preprint":false},{"pmid":"17989140","id":"PMC_17989140","title":"NPY Y1 receptor antagonist prevents NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters.","date":"2007","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17989140","citation_count":34,"is_preprint":false},{"pmid":"19193934","id":"PMC_19193934","title":"Appetitive and consummatory ingestive behaviors stimulated by PVH and perifornical area NPY injections.","date":"2009","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19193934","citation_count":34,"is_preprint":false},{"pmid":"2731031","id":"PMC_2731031","title":"Neuropeptide Y (NPY) and vasopressin (AVP) in the hypothalamo-neurohypophysial axis of salt-loaded or Brattleboro rats.","date":"1989","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2731031","citation_count":34,"is_preprint":false},{"pmid":"17979779","id":"PMC_17979779","title":"NPY and NPY receptors in vascular remodeling.","date":"2007","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17979779","citation_count":33,"is_preprint":false},{"pmid":"9802439","id":"PMC_9802439","title":"NPY-induced overfeeding suppresses hypothalamic NPY mRNA expression: potential roles of plasma insulin and leptin.","date":"1998","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/9802439","citation_count":33,"is_preprint":false},{"pmid":"11124136","id":"PMC_11124136","title":"Substance P and NPY differentially potentiate ATP and adrenergic stimulated vasopressin and oxytocin release.","date":"2001","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11124136","citation_count":33,"is_preprint":false},{"pmid":"22938859","id":"PMC_22938859","title":"Neuropeptide Y (NPY) in the extended amygdala is recruited during the transition to alcohol dependence.","date":"2012","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/22938859","citation_count":32,"is_preprint":false},{"pmid":"11896483","id":"PMC_11896483","title":"Appetite suppression based on selective inhibition of NPY receptors.","date":"2002","source":"International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity","url":"https://pubmed.ncbi.nlm.nih.gov/11896483","citation_count":31,"is_preprint":false},{"pmid":"18468678","id":"PMC_18468678","title":"Effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats.","date":"2008","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/18468678","citation_count":31,"is_preprint":false},{"pmid":"28315869","id":"PMC_28315869","title":"NPY and CGRP Inhibitor Influence on ERK Pathway and Macrophage Aggregation during Fracture Healing.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28315869","citation_count":30,"is_preprint":false},{"pmid":"34411658","id":"PMC_34411658","title":"Effect of depression and suicidal behavior on neuropeptide Y (NPY) and its receptors in the adult human brain: A postmortem study.","date":"2021","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34411658","citation_count":30,"is_preprint":false},{"pmid":"10544180","id":"PMC_10544180","title":"Parasites flicking the NPY gene on the host's switchboard: why NPY?","date":"1999","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10544180","citation_count":30,"is_preprint":false},{"pmid":"27856419","id":"PMC_27856419","title":"Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation.","date":"2016","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27856419","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46997,"output_tokens":6724,"usd":0.120926,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16046,"output_tokens":4884,"usd":0.101165,"stage2_stop_reason":"end_turn"},"total_usd":0.222091,"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\": 2022,\n      \"finding\": \"Cryo-EM/X-ray structures of human Y1, Y2, and Y4 receptors in complex with NPY or pancreatic polypeptide and Gi1 protein reveal distinct binding poses of the peptide ligand across receptor subtypes; the N-terminus of NPY forms extensive interactions with Y1 but not Y2 or Y4 receptors. A conserved aspartate in the third extracellular loop is essential for ligand binding in all four Y receptors but engages different arginine residues on the ligand depending on receptor subtype. Mutagenesis and functional studies confirmed subtype-specific receptor–peptide interactions.\",\n      \"method\": \"Cryo-EM/X-ray crystallography, receptor mutagenesis, functional assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structures combined with mutagenesis and functional validation in one rigorous study\",\n      \"pmids\": [\"35507650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPY Y1 receptor (Y1R) activation in the bed nucleus of the stria terminalis (BNST) suppresses binge alcohol drinking by enhancing inhibitory synaptic transmission specifically onto CRF neurons via a Gi-mediated, PKA-dependent postsynaptic mechanism. Chronic alcohol drinking leads to persistent alterations in Y1R function in this circuit in both mice and monkeys.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology, pharmacological receptor agonist/antagonist application, chemogenetics (DREADD), convergent physiological and behavioral assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (electrophysiology, chemogenetics, pharmacology) in a single study, replicated across two mammalian species\",\n      \"pmids\": [\"25751534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPY, but not AgRP or GABA, is uniquely required for the long-lasting (sustained) hunger drive generated by AgRP neuron stimulation. Selective deletion of NPY from AgRP neurons abolished optically-stimulated feeding; re-expression of NPY specifically in AgRP neurons rescued this phenotype.\",\n      \"method\": \"Conditional knockout (cell-type-specific NPY deletion), optogenetics, re-expression rescue experiment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective genetic deletion plus rescue by re-expression in the same cell type, clear behavioral readout\",\n      \"pmids\": [\"31033437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NPY potentiates phenylephrine-induced MAPK (ERK, JNK, p38) activation and PKC stimulation in primary neonatal cardiomyocytes via NPY Y5 receptors coupled to Gi protein in a pertussis-toxin-sensitive, calcium-independent manner; this synergism is specific to alpha-adrenergic (phenylephrine) but not angiotensin II stimulation.\",\n      \"method\": \"Neonatal cardiomyocyte culture, pharmacological agonist/antagonist studies, pertussis toxin treatment, Western blot (MAPK phosphorylation), PKC activity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro mechanistic dissection using pertussis toxin and receptor-selective ligands, multiple signaling readouts\",\n      \"pmids\": [\"10660688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"NPY-2 (Y2) receptor agonist NPY(13-36) and NPY-1 (Y1) agonist [Pro34]-NPY have opposite effects on high-threshold calcium currents in rat nodose ganglion neurons: Y2 activation decreases and Y1 activation increases peak transient high-threshold Ca2+ current amplitude.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology with selective receptor agonists\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological measurement with subtype-selective agonists, multiple neurons tested\",\n      \"pmids\": [\"8395583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NPY produced by human adrenal chromaffin cells locally enhances catecholamine secretion in an autocrine/paracrine manner, likely through the putative y3 receptor; Y1, Y2, Y4, and Y5 receptor mRNAs are expressed and functional (stimulate intracellular calcium rise) on chromaffin cells, but an NPY-immunoneutralizing antibody (not receptor-selective antagonists) markedly attenuated constitutive catecholamine release.\",\n      \"method\": \"RT-PCR, receptor-selective agonist/antagonist pharmacology, intracellular calcium measurement, immunoneutralization, RIA for catecholamines and NPY\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab; autocrine mechanism established but receptor identity partly uncertain\",\n      \"pmids\": [\"11739470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NPY promotes intestinal epithelial cell proliferation and suppresses apoptosis through PI3-K/pAkt (β-catenin) signaling and downregulation of miR-375; NPY knockout mice show reduced polyp formation in a DSS-induced colitis-tumorigenesis model.\",\n      \"method\": \"NPY knockout mouse model (in vivo), intestinal epithelial cell line (T84) in vitro, Western blot, PCNA/Ki67/TUNEL staining, miRNA expression analysis\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo with in vitro mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"27856419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATP-induced neuroproliferation in adult mouse olfactory epithelium requires NPY upregulation followed by Y1 receptor activation; intranasal purinergic receptor antagonism blocks NPY upregulation, and Y1 receptor antagonism blocks BrdU incorporation (proliferation).\",\n      \"method\": \"Intranasal pharmacological interventions, BrdU labeling, protein quantification (Western blot/IHC), purinergic receptor antagonist pre-treatment\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with two receptor blockers defining a signaling sequence, single lab\",\n      \"pmids\": [\"20211262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NPY elicits an attractive axon turning response in embryonic DRG growth cones and increases growth rate via the NPY Y1 receptor; Y1 receptor is expressed in neuroblasts of the rostral migratory stream; Y1- or Y2-receptor knockout mice have fewer proliferating precursor cells and neuroblasts in the subventricular zone/rostral migratory stream and fewer olfactory bulb neurons.\",\n      \"method\": \"Growth cone turning assay (live imaging, asymmetric gradient application), knockout mouse analysis, immunohistochemistry\",\n      \"journal\": \"Nutrition (Burbank, Los Angeles County, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (growth cone turning) plus genetic loss-of-function, single lab\",\n      \"pmids\": [\"18725084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NPY receptor binding requires a conserved aspartate residue in the third extracellular loop of all four Y receptors; the specific arginine on the NPY ligand that interacts with this aspartate differs depending on receptor subtype. These were determined by receptor mutagenesis, chimeric receptors, and modified peptide synthesis.\",\n      \"method\": \"Receptor mutagenesis, receptor chimeras, peptide analog synthesis, binding assays\",\n      \"journal\": \"Nutrition (Burbank, Los Angeles County, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis combined with binding assays, single review-style compilation but grounded in primary experimental data cited therein\",\n      \"pmids\": [\"18725084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human adipocytes predominantly express Y1 receptors (high-affinity sites for [125I]PYY and [125I](Leu31,Pro34)PYY with Y1 pharmacological profile) that mediate NPY's antilipolytic effect and stimulate leptin secretion; Y2 receptor expression is absent. Both effects were fully blocked by selective Y1 antagonists SR120819A and BIBP3226.\",\n      \"method\": \"RT-PCR, radioligand binding assay, [35S]GTPγS binding, lipolysis assay in isolated adipocytes, leptin secretion RIA, receptor antagonists\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays with selective antagonists, single lab\",\n      \"pmids\": [\"10858507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In the dorsal vagal complex (DVC), Y2 receptor activation suppresses TRH-stimulated gastric motility (mimicking peripheral PYY action), while Y1 receptor activation stimulates gastric motility from basal state; NPY effects depend on the motility state. PYY is rapidly converted to a Y2-selective agonist by DPP-IV (dipeptidyl aminopeptidase IV), explaining its predominant Y2 action in this context.\",\n      \"method\": \"Microinjection of receptor-selective agonists into DVC, in vivo gastric motility measurement\",\n      \"journal\": \"Neurogastroenterology and motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacological receptor dissection in vivo, single lab\",\n      \"pmids\": [\"9198086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Microinjection of Y1 receptor agonist [Leu31,Pro34]NPY into the nucleus tractus solitarius (NTS) produces vasodepressor and bradycardic responses; sub-picomolar doses of the Y2 agonist NPY(13-36) into NTS counteract these Y1-mediated vasodepressor responses, indicating a Y2/Y1 receptor-receptor interaction in the NTS.\",\n      \"method\": \"Stereotaxic microinjection of receptor-selective agonists, in vivo blood pressure and heart rate measurement\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor-selective dissection in vivo, single lab\",\n      \"pmids\": [\"8221064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NPY, acting through Y1 receptor (postsynaptic), potentiates phenylephrine (alpha1-adrenergic)-induced vasopressin and oxytocin release from hypothalamo-neurohypophysial explants in a sustained manner; Y1 agonist [Leu31,Pro34]-NPY increases VP and OT release but does not potentiate ATP-induced responses, indicating signaling specificity.\",\n      \"method\": \"Perifusion of hypothalamic-neurohypophysial explants, selective receptor agonists, RIA for vasopressin and oxytocin\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ex vivo pharmacological dissection with multiple agonists and readouts, single lab\",\n      \"pmids\": [\"11124136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the central amygdala (CEm), NPY Y2 receptors are located presynaptically (not on NPY neurons themselves) and their activation by Y2 agonist PYY3-36 reduces both inhibitory and excitatory synaptic transmission. Absence of NPY or Y2 receptors leads to increased GABA release specifically at inhibitory synapses in the CEm.\",\n      \"method\": \"Retrograde tract tracing, immunofluorescence, whole-cell patch-clamp electrophysiology, Y2 receptor knockout mice\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological dissection plus genetic KO, single lab\",\n      \"pmids\": [\"26365505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NPY antidepressant-like activity in the mouse forced swimming test is mediated by the Y1 receptor subtype: Y1 agonist [Leu31Pro34]PYY mimics NPY's anti-immobility effect, Y1 antagonists (BIBO3304, BIBP3226) block it, while Y2 agonist NPY(13-36) is inactive and Y2 antagonist BIIE0246 also reduces immobility (presumably by potentiating endogenous NPY release).\",\n      \"method\": \"Intracerebroventricular injection, mouse forced swimming test, receptor-selective agonists and antagonists, open field locomotion control\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with multiple selective ligands, single lab with robust behavioral read-out\",\n      \"pmids\": [\"11927186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NPY Y5 receptor activation mediates NPY-induced feeding and also contributes to decreases in brown adipose tissue temperature and energy expenditure (reduced oxygen consumption); Y1, Y2, and Y4 receptor agonists did not replicate these effects when given ICV.\",\n      \"method\": \"ICV injection of receptor-selective agonists, indirect calorimetry, implanted BAT temperature transponders, food intake measurement\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with multiple selective agonists, in vivo metabolic readouts, single lab\",\n      \"pmids\": [\"10564216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Systemic NPY reduces trigeminocervical complex (TCC) neuronal firing in response to dural nociceptive trigeminovascular activation via the NPY Y1 receptor; Y1 agonist mimics this effect and Y1 antagonist blocks it; Y2 and Y5 receptor agonists are ineffective.\",\n      \"method\": \"In vivo electrophysiology in anesthetized rats, systemic drug administration, receptor-selective agonists/antagonist\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo electrophysiological receptor dissection, single lab\",\n      \"pmids\": [\"27023421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NPY Y1 receptor antagonist (1229U91) blocks NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters, whereas Y5 receptor antagonist (CGP71683) does not; Y1 agonist but not Y5 agonist recapitulates the torpor effect, establishing Y1 receptor as necessary and sufficient for NPY-induced torpor.\",\n      \"method\": \"ICV injection, receptor-selective agonists/antagonists, body temperature telemetry, counterbalanced pharmacological design\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological necessity and sufficiency established with receptor-selective tools, single lab\",\n      \"pmids\": [\"17989140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NPY suppresses experimental autoimmune encephalomyelitis (EAE) via Y1 receptors: Y1 receptor agonists inhibit EAE induction, a Y1 antagonist causes earlier EAE onset, and ex vivo analysis shows Y1 signaling in autoreactive T cells shifts them toward Th2 and inhibits Th1 responses. Y5 agonist had no protective effect.\",\n      \"method\": \"EAE induction in C57BL/6 mice, pharmacological receptor agonist/antagonist treatment, ex vivo T cell restimulation, cytokine profiling\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in vivo plus ex vivo cellular mechanism, single lab\",\n      \"pmids\": [\"14500640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ascending skeletal interoceptive signaling downregulates hypothalamic NPY expression by inducing SMILE (small heterodimer partner-interacting leucine zipper protein), which binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY transcription. Reduced NPY signaling (via Y1R inhibition) accelerates free fatty acid oxidation in osteoblasts and rescues bone loss.\",\n      \"method\": \"EP4 sensory nerve knockout mice, hypothalamic molecular analysis, promoter binding (pCREB/SMILE complex), Y1R pharmacological inhibition, bone phenotype analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with molecular mechanistic follow-up identifying transcriptional complex, single lab\",\n      \"pmids\": [\"34468315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"NPY-like immunoreactivity is transported axonally in peripheral sympathetic neurons at a rapid rate (~3 mm/h), as demonstrated by accumulation above sciatic nerve ligations; reserpine depletes NPY from cardiac sympathetic nerve terminals (but not ganglia) in a manner dependent on intact nerve activity, distinguishing NPY storage/release from noradrenaline; 6-OHDA denervation depletes NPY from terminal fields but increases it in ganglia.\",\n      \"method\": \"Sciatic nerve ligation, reserpine and 6-OHDA pharmacology, radioimmunoassay, immunohistochemistry, HPLC\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct axonal transport measurement by ligation accumulation, multiple tissue pharmacological dissections, single lab\",\n      \"pmids\": [\"2858824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"NPY is co-stored with noradrenaline in large dense-cored vesicles and is released preferentially at high stimulation frequencies or strong sympathetic activation; NPY release is inhibited by prejunctional alpha-2 adrenoceptors and adenosine receptors, and facilitated by angiotensin II or beta-receptor activation. NPY acts prejunctionally to inhibit both NA and NPY release, and postjunctionally to potentiate vasoconstriction. A large amidated C-terminal portion of NPY is necessary for receptor binding, cAMP inhibition, and vasoconstrictor effects.\",\n      \"method\": \"Sympathetic nerve stimulation (peripheral vascular preparations), pharmacological pre/postjunctional dissection, RIA, cAMP assay, denervation supersensitivity experiments\",\n      \"journal\": \"Fundamental & clinical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and physiological assays establishing co-transmission mechanism, replicated across multiple vascular beds\",\n      \"pmids\": [\"2170253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NPY Y2 receptor activation (by NPY(13-36)) provides neuroprotection against AMPA-induced excitotoxicity in hippocampal slice cultures; endogenous NPY via Y1 receptors also contributes to neuroprotection in CA1; AMPA-induced injury increases BDNF in microglia, but this BDNF is not required for the Y2-mediated NPY neuroprotective effect.\",\n      \"method\": \"Organotypic hippocampal slice culture, AMPA excitotoxicity model, propidium iodide uptake, receptor-selective agonists/antagonists, TrkB-Fc and neutralizing antibody blockade, ELISA, immunohistochemistry\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor dissection in ex vivo model with multiple receptor blockers and pathway controls, single lab\",\n      \"pmids\": [\"18412629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Y1 receptor immunoreactivity is present in axonal processes of DRG neurons with centrifugal (peripheral) transport demonstrated by accumulation proximal to sciatic nerve crush lesions; Y1R co-localizes with CGRP in peripheral sensory axons and nerve endings near the epidermis.\",\n      \"method\": \"Immunohistochemistry, nerve crush/ligation lesion experiments, double-labeling (Y1R + CGRP), dorsal rhizotomy\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional lesion paradigm demonstrating axonal transport, single lab\",\n      \"pmids\": [\"11869028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NPY acting through Y1 receptors induces vasoconstriction and proliferation of pulmonary arterial smooth muscle cells via p38 and PKD pathway activation; selective Y1 antagonist BIBO 3304 blocks both effects; Y1 receptor expression is upregulated in pulmonary hypertension tissue.\",\n      \"method\": \"Wire myography, calcium imaging, Western blot (p38/PKD phosphorylation), thymidine incorporation proliferation assay, quantitative PCR, selective Y1 antagonist\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct signaling pathway dissection in primary human cells with selective antagonist, single lab\",\n      \"pmids\": [\"24779394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Insulin signaling specifically in NPY neurons controls food intake, energy expenditure, and GH/IGF-1 axis; selective deletion of the insulin receptor in NPY neurons (in both flies and mice) leads to increased energy stores, obesity, and impaired insulin sensitivity.\",\n      \"method\": \"Cell-type-specific conditional knockout of insulin receptor in NPY neurons (Drosophila and mouse), metabolic phenotyping\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic deletion with clean metabolic readouts, replicated across two species\",\n      \"pmids\": [\"28580287\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPY is a 36-amino-acid neuropeptide that is co-stored with noradrenaline in large dense-cored vesicles of sympathetic neurons and released preferentially at high stimulation frequencies; it signals through four Gi/Go-coupled Y receptors (Y1, Y2, Y4, Y5) whose structures have been resolved in complex with NPY and Gi1 protein, revealing subtype-specific binding poses and a conserved extracellular aspartate essential for ligand engagement. Via Y1 receptors NPY produces anxiolysis, antidepressant-like effects, vasodepressor responses in the NTS, torpor, and suppression of trigeminovascular pain; via Y2 receptors (presynaptically located) it inhibits excitatory and inhibitory synaptic transmission in the amygdala and provides hippocampal neuroprotection; via Y5 receptors it mediates sustained feeding and decreases energy expenditure; NPY Y1R activation in BNST CRF neurons suppresses binge alcohol drinking through a Gi/PKA-dependent postsynaptic mechanism. In the hypothalamus, NPY expression in AgRP neurons uniquely sustains hunger after AgRP neuron activation, and is suppressed by a SMILE–pCREB transcriptional complex downstream of skeletal interoceptive EP4 signaling. Insulin receptor signaling within NPY neurons regulates energy balance, and NPY promotes intestinal epithelial proliferation via PI3-K/β-catenin signaling with miR-375 downregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPY is a sympathetic and central neuropeptide that couples neuronal activity to feeding, energy balance, autonomic control, and tissue proliferation by acting through a family of Gi/Go-coupled Y receptors [#22, #0]. In sympathetic neurons NPY is co-stored with noradrenaline in large dense-cored vesicles, transported axonally at rapid rates, and released preferentially during high-frequency or strong sympathetic activation; its amidated C-terminus is required for receptor binding, cAMP inhibition, and vasoconstrictor effects, and it acts both prejunctionally to inhibit transmitter release and postjunctionally to potentiate vasoconstriction [#21, #22]. Structural and mutagenesis studies define how NPY engages the Y1, Y2, and Y4 receptors with distinct binding poses, with a conserved third-extracellular-loop aspartate essential across all subtypes engaging different ligand arginines depending on receptor subtype [#0, #9]. Receptor subtype dictates physiology: Y1 signaling mediates antidepressant-like behavior, NTS vasodepressor responses, torpor, suppression of trigeminovascular firing, and suppression of binge alcohol drinking via a Gi/PKA-dependent enhancement of inhibition onto BNST CRF neurons [#15, #12, #18, #17, #1]; presynaptic Y2 receptors suppress excitatory and inhibitory synaptic transmission in the amygdala and confer hippocampal neuroprotection [#14, #23]; and Y5 receptors drive feeding and reduced energy expenditure [#16]. In the hypothalamus NPY expression in AgRP neurons is uniquely required to sustain hunger after AgRP neuron activation and is transcriptionally repressed by a SMILE–pCREB complex downstream of skeletal interoceptive EP4 signaling, while insulin receptor signaling within NPY neurons governs energy stores and the GH/IGF-1 axis [#2, #20, #26]. Beyond neuronal signaling, NPY promotes epithelial and precursor cell proliferation, driving intestinal epithelial growth via PI3-K/β-catenin signaling with miR-375 downregulation and Y1-dependent neuroproliferation [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Established NPY as an axonally trafficked sympathetic neuropeptide whose storage and depletion behavior is distinct from noradrenaline, raising the question of how it is released.\",\n      \"evidence\": \"Sciatic nerve ligation, reserpine/6-OHDA pharmacology, RIA and IHC in peripheral sympathetic neurons\",\n      \"pmids\": [\"2858824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define release kinetics or receptor targets\", \"Vesicular storage with noradrenaline inferred pharmacologically\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Defined NPY as a sympathetic co-transmitter released at high stimulation frequencies acting pre- and postjunctionally, and identified the amidated C-terminus as the functional binding determinant.\",\n      \"evidence\": \"Sympathetic nerve stimulation in vascular preparations, pre/postjunctional pharmacology, cAMP assay across multiple vascular beds\",\n      \"pmids\": [\"2170253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor subtype assignments not yet molecular\", \"Did not resolve atomic basis of receptor engagement\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrated that Y1 and Y2 receptors exert opposite effects on the same target, establishing subtype-specific and antagonistic NPY signaling in autonomic circuits.\",\n      \"evidence\": \"Patch-clamp of nodose ganglion Ca2+ currents with subtype-selective agonists; NTS microinjection with blood pressure/heart rate readouts\",\n      \"pmids\": [\"8395583\", \"8221064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor localization (pre- vs postsynaptic) not resolved\", \"Downstream effectors not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed NPY/PYY gastric motility effects are state-dependent and split between Y1 and Y2 receptors, with DPP-IV conversion biasing PYY toward Y2 action.\",\n      \"evidence\": \"DVC microinjection of receptor-selective agonists with in vivo gastric motility measurement\",\n      \"pmids\": [\"9198086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular circuit underlying motility state-dependence undefined\", \"No structural basis for ligand selectivity\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified Y5-Gi coupled cross-talk with alpha-adrenergic signaling in cardiomyocytes and Y1-mediated antilipolytic/leptin-stimulating action in adipocytes, extending NPY signaling to peripheral metabolic and cardiac targets.\",\n      \"evidence\": \"Cardiomyocyte cultures with pertussis toxin and MAPK/PKC readouts; adipocyte radioligand binding, GTPγS, lipolysis and leptin assays with Y1 antagonists\",\n      \"pmids\": [\"10660688\", \"10858507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance in vivo not established in these studies\", \"Y5 versus Y1 selectivity tissue-dependent\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed autocrine/paracrine NPY action enhancing catecholamine secretion in chromaffin cells and Y1-dependent potentiation of vasopressin/oxytocin release, showing NPY amplifies neuroendocrine output.\",\n      \"evidence\": \"RT-PCR, calcium imaging, immunoneutralization in chromaffin cells; perifused hypothalamo-neurohypophysial explants with selective agonists\",\n      \"pmids\": [\"11739470\", \"11124136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Putative y3 receptor identity uncertain\", \"Single-lab findings without reciprocal validation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped Y1-receptor protein to peripheral sensory axons co-localizing with CGRP and pinned antidepressant-like behavioral effects to the Y1 subtype.\",\n      \"evidence\": \"IHC with nerve crush/rhizotomy axonal transport paradigm; ICV ligand pharmacology in the forced swimming test\",\n      \"pmids\": [\"11869028\", \"11927186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circuit linking sensory Y1R to nociception not defined\", \"Behavioral receptor assignment from pharmacology only\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended NPY signaling to immune regulation, showing Y1 receptors on autoreactive T cells bias toward Th2 and suppress autoimmune neuroinflammation.\",\n      \"evidence\": \"EAE induction in mice with Y1/Y5 agonist and antagonist treatment, ex vivo T cell restimulation and cytokine profiling\",\n      \"pmids\": [\"14500640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect T cell action not fully separated\", \"Single-lab pharmacological epistasis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established Y1 receptor as necessary and sufficient for NPY-induced torpor, separating thermoregulatory control from Y5-mediated feeding.\",\n      \"evidence\": \"ICV receptor-selective agonist/antagonist with body temperature telemetry in Siberian hamsters\",\n      \"pmids\": [\"17989140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector circuit downstream of Y1R undefined\", \"Species-specific torpor model\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the conserved aspartate–arginine binding contact for ligand engagement and showed NPY drives neuroprotection and neuroproliferation/axon guidance through Y1 and Y2 receptors.\",\n      \"evidence\": \"Receptor mutagenesis/chimeras and peptide analogs; growth cone turning assays and Y1/Y2 knockout analysis; hippocampal slice excitotoxicity model with receptor blockers\",\n      \"pmids\": [\"18725084\", \"18412629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic structure of binding not yet resolved at this stage\", \"Neuroprotective downstream effectors only partly defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected Y1 signaling to vascular smooth muscle proliferation and vasoconstriction via p38/PKD, implicating NPY in pulmonary hypertension.\",\n      \"evidence\": \"Myography, calcium imaging, Western blot and proliferation assays in human pulmonary arterial smooth muscle with selective Y1 antagonist\",\n      \"pmids\": [\"24779394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role in disease progression in vivo not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localized Y2 receptors presynaptically in the amygdala and defined a Y1-Gi/PKA postsynaptic mechanism onto BNST CRF neurons controlling binge drinking.\",\n      \"evidence\": \"Patch-clamp electrophysiology, tract tracing, Y2 knockout mice; chemogenetics and pharmacology across mice and monkeys\",\n      \"pmids\": [\"26365505\", \"25751534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term circuit remodeling after chronic alcohol incompletely mapped\", \"Y2 presynaptic target neurons partly undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed insulin receptor signaling within NPY neurons is a cell-autonomous regulator of energy stores, obesity, and the GH/IGF-1 axis, conserved across flies and mice.\",\n      \"evidence\": \"Cell-type-specific insulin receptor knockout in NPY neurons with metabolic phenotyping in Drosophila and mouse\",\n      \"pmids\": [\"28580287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream transcriptional response in NPY neurons not defined\", \"Link to NPY peptide output not directly measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated NPY peptide itself is uniquely required to sustain hunger driven by AgRP neurons, distinguishing it from co-expressed AgRP and GABA.\",\n      \"evidence\": \"Cell-type-specific NPY deletion plus re-expression rescue with optogenetic feeding readout\",\n      \"pmids\": [\"31033437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor subtype mediating sustained hunger not identified here\", \"Temporal dynamics of NPY release undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the SMILE–pCREB transcriptional complex repressing hypothalamic Npy downstream of skeletal interoceptive EP4 signaling, linking bone-derived signals to NPY-mediated metabolic control.\",\n      \"evidence\": \"EP4 sensory nerve knockout mice, promoter binding analysis, Y1R inhibition and bone phenotyping\",\n      \"pmids\": [\"34468315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy detail limited\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved atomic-resolution Y1/Y2/Y4–NPY/PP–Gi1 structures, revealing subtype-specific binding poses and confirming the conserved aspartate binding determinant.\",\n      \"evidence\": \"Cryo-EM/X-ray crystallography with receptor mutagenesis and functional assays\",\n      \"pmids\": [\"35507650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Y5 receptor structure not resolved\", \"Conformational basis of biased signaling not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NPY release dynamics, receptor subtype switching, and tissue-specific Gi effectors are integrated to produce the divergent feeding, autonomic, behavioral, and proliferative outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking subtype selection to physiological context\", \"Y3/y5 receptor roles incompletely defined\", \"Transcriptional control of NPY across tissues only partly mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 22, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 10, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [22, 21]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [22, 21, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 14, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NPY1R\", \"NPY2R\", \"NPY4R\", \"NPY5R\", \"GNAI1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}