{"gene":"LEPR","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"LEPR (OB-R) was identified as a leptin-binding receptor by expression cloning from mouse choroid plexus using a leptin-alkaline phosphatase fusion protein as a probe. OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor.","method":"cDNA expression library screening with leptin-AP fusion protein; ligand binding assay with [125I]leptin; sequence homology analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — original receptor identification by expression cloning with direct ligand binding validation; foundational paper replicated widely","pmids":["8548812"],"is_preprint":false},{"year":1996,"finding":"A point mutation in the rat fatty (fa) allele of Lepr (Gln269Pro substitution caused by A→C nucleotide change at position 880) greatly reduces leptin binding at the cell surface, establishing that this single residue in the extracellular domain is critical for leptin binding and that loss of Lepr function causes the obese phenotype.","method":"PCR-based mutagenesis to introduce fa mutation into mouse Lepr cDNA; transient transfection; cell-surface leptin binding assay; genetic co-segregation analysis in 1028 meioses","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis + binding assay + genetic co-segregation across large cross; multiple orthogonal methods in one study","pmids":["8690163"],"is_preprint":false},{"year":1997,"finding":"The long form of OB-R mediates ligand-induced activation of STAT1, STAT3, and STAT5 and stimulates transcription via IL-6 and hematopoietin receptor responsive gene elements. Deletion and tyrosine substitution mutagenesis identified two distinct regions of the intracellular domain required for signaling. Chimeric receptor experiments showed that aggregation of two OB-R intracellular domains is sufficient for ligand-induced activation, providing evidence for receptor homo-oligomerization.","method":"Cytoplasmic domain deletion and tyrosine substitution mutagenesis; G-CSF receptor/OB-R chimera signaling assays; STAT activation reporter assays; dominant negative repression experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis combined with chimeric receptor reconstitution and multiple signaling readouts in one study","pmids":["9020115"],"is_preprint":false},{"year":1997,"finding":"OB-R undergoes spontaneous homo-oligomerization (demonstrated by co-immunoprecipitation of two differently epitope-tagged OB-R molecules), and leptin signaling does not require interaction with gp130 or LIFR, as leptin stimulation does not induce tyrosine phosphorylation of gp130 or LIFR.","method":"Co-immunoprecipitation of differentially epitope-tagged OB-R constructs; tyrosine phosphorylation assays; Ba/F3 cell transfection and proliferation assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with tagged constructs plus functional signaling assays; independently consistent with White et al. 1997","pmids":["9038364"],"is_preprint":false},{"year":1997,"finding":"Stimulation of the long form of OB-R leads to STAT3 tyrosine phosphorylation and p42ERK2 activation, but unlike gp130, OB-R long form does not induce tyrosine phosphorylation of the SHP-2 phosphatase. The truncated short form of OB-R expressed in db/db mice fails to activate STAT3, establishing that the long intracellular domain is required for STAT3 signaling.","method":"Tyrosine phosphorylation assays; STAT3 immunoprecipitation; ERK activation assays; comparison of long vs. truncated OB-R isoforms","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct comparison of receptor isoforms with multiple signaling pathway readouts; consistent with White et al. 1997","pmids":["9003804"],"is_preprint":false},{"year":1998,"finding":"The long splice variant of the leptin receptor (Ob-Rb) is expressed in hindbrain neuronal regions including the nucleus of the solitary tract, lateral parabrachial nucleus, and medullary reticular nucleus, while short receptor splice variants are abundantly expressed in leptomeninges and choroid plexus, establishing anatomical segregation of functional isoforms in the rodent brain.","method":"In situ hybridization with isoform-specific probes in mouse and rat hindbrain","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by in situ hybridization with isoform discrimination; single lab but clear isoform-specific pattern","pmids":["9421394"],"is_preprint":false},{"year":2001,"finding":"LEPR-mediated feedback regulation of leptin (Lep) mRNA expression in brown adipose tissue (BAT) operates primarily through CNS-mediated effects on sympathetic nervous system (SNS) activity, whereas leptin expression in white adipose tissue (WAT) is regulated through mechanisms not directly dependent on SNS activity. Metabolic rate (SNS surrogate) explained 87% of variation in BAT-Lep mRNA.","method":"Genetic segregation of Lepr(fa) allele in rat pups; artificial rearing under thermoneutral conditions; oral norepinephrine administration; quantitative Lep mRNA measurement in BAT and WAT; plasma leptin measurement","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetically controlled experimental system with multiple manipulations and quantitative molecular readouts; single lab","pmids":["11160998"],"is_preprint":false},{"year":2014,"finding":"HIF-1α directly activates leptin receptor (Ob-R) transcription by binding to a hypoxia-responsive element (HRE) at -828/-832 in the Ob-R gene promoter in pancreatic cancer cells. HIF-1α silencing reduces Ob-R expression both in vitro and in xenograft models.","method":"HIF-1α overexpression and siRNA knockdown; chromatin immunoprecipitation (ChIP) for HRE binding; xenograft mouse models with HIF-1α inhibition; immunohistochemistry","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus loss-of-function in vitro and in vivo; single lab","pmids":["25130171"],"is_preprint":false},{"year":2017,"finding":"LepR-mediated transport of leptin across brain barriers (endothelial and choroid plexus epithelial cells) controls food reward but is not required for homeostatic feeding control. Selective deletion of LepR in brain endothelial and epithelial cells caused hyperphagia and increased sensitivity to food reward on high-fat diet, while leaving median eminence and tanycyte LepR expression intact.","method":"Conditional LepR knockout in brain endothelial/epithelial cells (LepRbeKO mice); perfusion studies measuring brain leptin uptake; behavioral testing on high-fat diet; body weight and food intake measurements","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with brain uptake perfusion studies and behavioral phenotyping; multiple orthogonal readouts","pmids":["29254602"],"is_preprint":false},{"year":2021,"finding":"Hypothalamic tanycytes express functional LepR that responds to leptin by triggering Ca2+ waves and target protein phosphorylation. Tanycytic transcytotic transport of leptin into the brain requires activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, causing increased food intake, lipogenesis, and glucose intolerance through attenuated insulin secretion by pancreatic β-cells.","method":"Multiple complementary mouse models with selective LepR deletion in tanycytes; Ca2+ imaging; protein phosphorylation assays; leptin transport measurement; metabolic phenotyping; insulin secretion assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary genetic models, Ca2+ signaling assays, transport measurements, and metabolic phenotyping; multiple orthogonal methods","pmids":["34341568"],"is_preprint":false},{"year":2021,"finding":"A GABAergic population of hypothalamic LepRb neurons co-expressing Glp1r (LepRbGlp1r neurons) plays a crucial role in suppression of food intake by leptin. Ablating Lepr from LepRbGlp1r neurons provoked hyperphagic obesity without impairing energy expenditure. Restoration of Lepr in GABAergic neurons required Lepr expression in Glp1r-expressing neurons to improve energy balance.","method":"Single-nucleus RNA-seq of enriched hypothalamic LepRb cells; cell-type-specific Lepr ablation; Lepr reactivation in otherwise Lepr-null mice; body weight and food intake measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-nucleus RNA-seq identification combined with conditional KO and rescue genetic epistasis experiments with defined phenotypic readouts","pmids":["37581939"],"is_preprint":false},{"year":2021,"finding":"A subpopulation of lateral hypothalamic GABAergic LEPR-expressing neurons (LHLEPR) specifically drives appetitive but not consummatory behaviors. Ablation of LHLEPR neurons prevented appetitive learning in Pavlovian conditioning but did not affect feeding. LHLEPR→VTA projections bidirectionally modulate reward-related behaviors, and chemogenetic inhibition of LHLEPR neurons attenuates cocaine sensitization but not cocaine conditioned place preference.","method":"Neuron-specific ablation; Pavlovian conditioning paradigm; optogenetic activation/inhibition; chemogenetic (DREADD) manipulation; food intake and weight measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type specific ablation, optogenetics, and chemogenetics with multiple behavioral paradigms identifying circuit-level function","pmids":["34433027"],"is_preprint":false},{"year":2016,"finding":"Leptin binding to OB-R inhibits leptin transport across a human in vitro BBB model (hCMEC/D3 cells) — specifically, an OB-R-neutralizing antibody that blocks leptin-OB-R binding and STAT3 phosphorylation does NOT inhibit leptin transcytosis, establishing that OB-R signaling is not required for leptin transport across human endothelial cells. LRP-2 (megalin) is expressed in these cells and may serve as the primary leptin transporter.","method":"In vitro human BBB model (hCMEC/D3); OB-R neutralizing antibody (9F8) treatment; STAT3 phosphorylation assay; transcytosis/transport measurement; endocytosis inhibitor assays; LRP-2 expression analysis","journal":"Journal of neuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional inhibition of OB-R with validated antibody plus transport measurements; negative result about OB-R transport role is well-controlled","pmids":["27037668"],"is_preprint":false},{"year":2018,"finding":"LepR mutation replacing the three intracellular tyrosine residues (Tyr985, Tyr1077, Tyr1138) with phenylalanine (Y123F mice) causes follicle loss and infertility in female mice, associated with elevated phosphorylation of Akt, mTOR, S6K1, and eIF4B (PTEN/PI3K/mTOR pathway activation) in ovaries, establishing that LepR tyrosine signaling normally suppresses the PTEN/PI3K/mTOR pathway in ovarian follicles.","method":"Homologous gene targeting to generate Y123F mice; reproductive phenotyping; AMH measurement; follicle counting; western blotting for pathway components","journal":"Gynecological endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted mutagenesis of specific tyrosine residues with molecular pathway analysis; single lab","pmids":["30145913"],"is_preprint":false},{"year":2021,"finding":"LEPR interacts with ANXA7 (Annexin A7) in hepatocellular carcinoma cells (co-immunoprecipitation), and mechanistically LEPR regulates ERK1/2 and JAK2/STAT3 signaling via ANXA7.","method":"Co-immunoprecipitation; western blotting; immunofluorescence; functional assays (proliferation, migration, invasion, apoptosis); siRNA knockdown","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction; mechanistic downstream pathway inferred from knockdown experiments without reconstitution; single lab","pmids":["33397392"],"is_preprint":false},{"year":2023,"finding":"Leptin/obR signaling promotes M1 macrophage polarization via phosphorylation of the long isoform of obR and activation of JNK/STAT3/AKT signaling pathways; leptin-mediated M1 macrophage activity increases CXCL2 production and neutrophil recruitment in obesity-related airway inflammation.","method":"db/db obR-deficient mice; obR blockade (Allo-Aca); bone marrow-derived macrophage (BMDM) in vitro experiments; flow cytometry; western blotting; ELISA; BALF cytokine analysis","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deficiency model combined with pharmacological blockade and in vitro mechanistic experiments; multiple orthogonal methods; single lab","pmids":["37488474"],"is_preprint":false},{"year":2024,"finding":"GABAergic LepRGlp1r neurons in the dorsomedial hypothalamus (DMH) mediate suppression of food intake and body weight by a GLP-1R/LepR dual agonist. Ablating Lepr in Glp1r-expressing neurons abrogated the dual agonist's food intake suppression. Reactivation of Glp1r in Lepr neurons on an otherwise Glp1r-null background was sufficient to restore dual agonist efficacy. LepRGlp1r neurons exist in non-human primate DMH.","method":"Conditional Lepr ablation in Glp1r neurons; Glp1r reactivation in Lepr neurons; pharmacological dual agonist treatment; food intake and body weight measurement; immunohistochemistry in NHP","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and genetic rescue (reactivation) provide bidirectional epistasis evidence for circuit-level mechanism; translational validation in NHP","pmids":["39630884"],"is_preprint":false},{"year":2024,"finding":"GIPR and Lepr strongly co-localize in pancreatic β-cells but not in hypothalamus or hindbrain. Loss of GIPR in Lepr-expressing cells abolishes the superior glycemic effects of GIPR:GLP-1R co-agonism over single GLP-1R agonism, but does not affect body weight or food intake, establishing that LepR+ pancreatic cells (not brain neurons) mediate the glycemic but not anorectic actions of GIP.","method":"Single-cell RNA-seq co-expression analysis; Lepr-specific Gipr conditional knockout; metabolic phenotyping; GIP and dual agonist pharmacology in DIO mice","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with pharmacological dissection and scRNA-seq; multiple orthogonal readouts establishing tissue-specific functional role","pmids":["38492844"],"is_preprint":false}],"current_model":"LEPR (OB-R) is a single-pass class I cytokine receptor that binds leptin and signals as a homo-oligomer; the long isoform (LepRb) activates JAK2-STAT3, MAPK/ERK, and PI3K/AKT pathways via two critical intracellular tyrosine-containing regions, whereas short isoforms lack STAT3-activating capacity; in the brain, LepRb in specific GABAergic hypothalamic neuron populations (including Glp1r-co-expressing DMH neurons) suppresses food intake and body weight, while LepR in tanycytes and blood-brain barrier cells mediates transcytotic leptin transport into the brain, and LepR in pancreatic β-cells contributes to glucose control downstream of GIP signaling."},"narrative":{"mechanistic_narrative":"LEPR (OB-R) is a single membrane-spanning class I cytokine receptor, structurally related to gp130 and the G-CSF/LIF receptors, that serves as the principal signal-transducing receptor for leptin and thereby links peripheral energy stores to central control of food intake and metabolism [PMID:8548812]. A single extracellular residue (Gln269) is critical for high-affinity leptin binding, and its loss in the rat fatty (fa) allele abolishes surface binding and produces obesity, establishing LEPR loss-of-function as causal for the obese phenotype [PMID:8690163]. LEPR signals as a spontaneously formed homo-oligomer—aggregation of two intracellular domains is sufficient for activation, and signaling proceeds without recruitment of gp130 or LIFR [PMID:9020115, PMID:9038364]. The long isoform (Ob-Rb) activates STAT1/3/5, ERK/MAPK, and, through its intracellular tyrosine residues (Tyr985, Tyr1077, Tyr1138), the PI3K/AKT/mTOR axis, whereas truncated short isoforms expressed in db/db animals fail to activate STAT3 [PMID:9020115, PMID:9003804, PMID:30145913]. Functional isoforms are anatomically segregated in the brain, with Ob-Rb concentrated in hindbrain neuronal nuclei and short variants in choroid plexus and leptomeninges [PMID:9421394]. In the brain, leptin acts through distinct LepRb neuron populations: GABAergic dorsomedial hypothalamic neurons co-expressing Glp1r suppress food intake and body weight and mediate the efficacy of GLP-1R/LepR dual agonists [PMID:37581939, PMID:39630884], while a lateral hypothalamic GABAergic LEPR population drives appetitive reward behaviors via projections to the VTA [PMID:34433027]. LepR additionally governs leptin entry into the brain: tanycytic transcytosis requires sequential activation of a LepR-EGFR complex, and its loss blocks leptin entry and produces hyperphagia, lipogenesis, and glucose intolerance [PMID:34341568], while LepR in brain barrier endothelial/epithelial cells controls food reward distinct from homeostatic feeding [PMID:29254602]. LepR+ pancreatic cells, where LepR co-localizes with GIPR, mediate the glycemic but not the anorectic actions of incretin co-agonism [PMID:38492844]. Beyond CNS and metabolic roles, LepR transcription is induced by HIF-1α via a promoter HRE in cancer cells [PMID:25130171], and leptin/OB-R signaling promotes M1 macrophage polarization through JNK/STAT3/AKT, linking it to obesity-related inflammation [PMID:37488474].","teleology":[{"year":1995,"claim":"Established the molecular identity of the leptin receptor, answering what cell-surface protein transduces the leptin signal and placing it in the class I cytokine receptor family.","evidence":"expression cloning from mouse choroid plexus with a leptin-AP fusion probe and [125I]leptin binding","pmids":["8548812"],"confidence":"High","gaps":["Did not resolve which isoform mediates intracellular signaling","Binding stoichiometry and oligomeric state not addressed"]},{"year":1996,"claim":"Connected receptor function to phenotype by showing a single extracellular residue governs leptin binding and that its loss causes obesity.","evidence":"introduction of the rat fa Gln269Pro mutation into Lepr cDNA, cell-surface binding assays, and co-segregation across 1028 meioses","pmids":["8690163"],"confidence":"High","gaps":["Did not define the full leptin-binding interface","Downstream signaling consequences of binding loss not measured here"]},{"year":1997,"claim":"Defined the signaling logic of LEPR: it homo-oligomerizes independently of gp130/LIFR and uses two distinct intracellular regions to activate STATs and ERK, with the long domain required for STAT3.","evidence":"deletion/tyrosine-substitution mutagenesis, G-CSFR/OB-R chimeras, reciprocal Co-IP of tagged receptors, and STAT/ERK readouts across three studies","pmids":["9020115","9038364","9003804"],"confidence":"High","gaps":["Did not map individual tyrosine residues to specific outputs in vivo","JAK kinase identity and recruitment not resolved in these studies"]},{"year":1998,"claim":"Showed that long and short LEPR isoforms are anatomically segregated in the brain, implying region-specific signaling versus transport roles.","evidence":"isoform-specific in situ hybridization in mouse and rat hindbrain","pmids":["9421394"],"confidence":"Medium","gaps":["Expression mapping does not establish functional roles per region","Single-lab localization without functional perturbation"]},{"year":2001,"claim":"Demonstrated that LEPR-dependent feedback on leptin production is CNS-routed via the sympathetic nervous system in brown but not white fat, framing LEPR within a closed-loop energy-balance circuit.","evidence":"fa-allele segregation in rat pups, thermoneutral artificial rearing, norepinephrine administration, and Lep mRNA quantification","pmids":["11160998"],"confidence":"Medium","gaps":["WAT regulatory mechanism left undefined","Indirect inference of SNS activity from metabolic rate"]},{"year":2016,"claim":"Dissociated leptin transport from OB-R signaling at the human BBB, showing OB-R signaling is dispensable for transcytosis and implicating LRP-2/megalin instead.","evidence":"human hCMEC/D3 BBB model with OB-R-neutralizing antibody, STAT3 phosphorylation, and transcytosis assays","pmids":["27037668"],"confidence":"Medium","gaps":["Did not directly prove LRP-2 mediates transport","In vitro human model may differ from rodent barrier biology"]},{"year":2014,"claim":"Identified a transcriptional input to LEPR by showing HIF-1α directly drives Ob-R promoter activity in cancer cells.","evidence":"HIF-1α overexpression/knockdown, ChIP at the -828/-832 HRE, and xenograft models","pmids":["25130171"],"confidence":"Medium","gaps":["Functional consequence of HIF-driven LEPR in tumor biology not fully defined","Single-lab finding restricted to pancreatic cancer cells"]},{"year":2017,"claim":"Showed brain-barrier LepR controls leptin transport governing food reward, separating this function from homeostatic feeding control.","evidence":"endothelial/epithelial-specific LepR knockout, brain leptin uptake perfusion, and high-fat-diet behavioral testing","pmids":["29254602"],"confidence":"High","gaps":["Molecular transport machinery downstream of LepR not defined","Reward circuitry linkage inferred behaviorally"]},{"year":2021,"claim":"Defined tanycytic LepR as a leptin-responsive, transport-gating receptor requiring a sequential LepR-EGFR complex, controlling both brain leptin entry and systemic glucose handling.","evidence":"multiple tanycyte-specific LepR deletion models, Ca2+ imaging, phosphorylation assays, transport measurement, and metabolic/insulin-secretion phenotyping","pmids":["34341568"],"confidence":"High","gaps":["Precise molecular coupling between LepR and EGFR not structurally resolved","Relationship to barrier-cell transport pathway not reconciled"]},{"year":2021,"claim":"Resolved hypothalamic LepRb circuitry into functionally distinct GABAergic populations: Glp1r-co-expressing neurons suppress feeding, while lateral hypothalamic LEPR neurons drive appetitive reward.","evidence":"single-nucleus RNA-seq, cell-type-specific ablation/reactivation, optogenetics, chemogenetics, and behavioral paradigms across two studies","pmids":["37581939","34433027"],"confidence":"High","gaps":["Intracellular signaling distinguishing these populations not defined","Connectivity between feeding and reward LepR populations unresolved"]},{"year":2018,"claim":"Assigned a reproductive function to LEPR tyrosine signaling, showing the three intracellular tyrosines normally restrain the PI3K/mTOR pathway in ovarian follicles.","evidence":"Y123F (Tyr985/1077/1138-to-Phe) knock-in mice with follicle counting and pathway western blotting","pmids":["30145913"],"confidence":"Medium","gaps":["Cannot attribute the phenotype to a single tyrosine residue","Cell-autonomous versus systemic contribution to infertility not separated"]},{"year":2023,"claim":"Extended LEPR function to immunity, showing leptin/OB-R signaling drives M1 macrophage polarization and neutrophil recruitment in obesity-related airway inflammation.","evidence":"db/db obR-deficient mice, pharmacological obR blockade, and BMDM in vitro signaling/cytokine assays","pmids":["37488474"],"confidence":"Medium","gaps":["Direct versus systemic effects of obR loss not fully separated","Single-lab finding within a specific inflammation context"]},{"year":2024,"claim":"Pinpointed the tissue sites of incretin co-agonist action relative to LepR: DMH GABAergic LepRGlp1r neurons mediate anorexia, while LepR+ pancreatic cells expressing GIPR mediate the glycemic benefit.","evidence":"conditional Lepr/Gipr knockouts and Glp1r reactivation, scRNA-seq co-expression, dual-agonist pharmacology, and NHP immunohistochemistry across two studies","pmids":["39630884","38492844"],"confidence":"High","gaps":["Signaling crosstalk between LepR and GIPR/GLP-1R in the same cells not defined","Pancreatic LepR's own ligand-dependent role not isolated from GIPR effects"]},{"year":null,"claim":"How LEPR signaling outputs are differentially wired across the distinct neuronal, glial, barrier, pancreatic, and immune cell types to produce tissue-specific physiology remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the ligand-bound oligomeric receptor in the corpus","Mechanism coupling LepR to EGFR and to incretin receptors not defined","How identical intracellular tyrosines yield divergent outcomes across tissues is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9,17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,10,11,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8,9]}],"complexes":["LEPR homo-oligomer","LepR-EGFR complex"],"partners":["LEP","EGFR","GIPR","ANXA7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48357","full_name":"Leptin receptor","aliases":["HuB219","OB receptor","OB-R"],"length_aa":1165,"mass_kda":132.5,"function":"Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (By similarity) (PubMed:9537324). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:12504075, PubMed:25060689, PubMed:8805376). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production (By similarity) May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis. 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Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31983119","citation_count":11,"is_preprint":false},{"pmid":"19608021","id":"PMC_19608021","title":"Inflammatory state and stress condition in weight-lowering Lys109Arg LEPR gene polymorphism carriers.","date":"2009","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/19608021","citation_count":11,"is_preprint":false},{"pmid":"15131772","id":"PMC_15131772","title":"Association of Ob-R gene polymorphism and insulin resistance in Japanese men.","date":"2004","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/15131772","citation_count":11,"is_preprint":false},{"pmid":"35801948","id":"PMC_35801948","title":"Screening of non-syndromic early-onset child and adolescent obese patients in terms of LEP, LEPR, MC4R and POMC gene variants by next-generation sequencing.","date":"2022","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/35801948","citation_count":11,"is_preprint":false},{"pmid":"28969001","id":"PMC_28969001","title":"Leptin/OB-R pathway promotes IL-4 secretion from B lymphocytes and induces salivary gland epithelial cell apoptosis in Sjögren's syndrome.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28969001","citation_count":11,"is_preprint":false},{"pmid":"38704700","id":"PMC_38704700","title":"The Long Non-Coding RNA Obesity-Related (Obr) Contributes To Lipid Metabolism Through Epigenetic Regulation.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38704700","citation_count":10,"is_preprint":false},{"pmid":"38492844","id":"PMC_38492844","title":"Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.","date":"2024","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38492844","citation_count":10,"is_preprint":false},{"pmid":"34452542","id":"PMC_34452542","title":"Association of PON1, LEP and LEPR Polymorphisms with Susceptibility to Breast Cancer: A Meta-Analysis.","date":"2021","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/34452542","citation_count":10,"is_preprint":false},{"pmid":"30145913","id":"PMC_30145913","title":"Follicle loss and PTEN/PI3K/mTOR signaling pathway activated in LepR-mutated mice.","date":"2018","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30145913","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54101,"output_tokens":4872,"usd":0.117692,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13185,"output_tokens":4498,"usd":0.089188,"stage2_stop_reason":"end_turn"},"total_usd":0.20688,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"LEPR (OB-R) was identified as a leptin-binding receptor by expression cloning from mouse choroid plexus using a leptin-alkaline phosphatase fusion protein as a probe. OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor.\",\n      \"method\": \"cDNA expression library screening with leptin-AP fusion protein; ligand binding assay with [125I]leptin; sequence homology analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original receptor identification by expression cloning with direct ligand binding validation; foundational paper replicated widely\",\n      \"pmids\": [\"8548812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A point mutation in the rat fatty (fa) allele of Lepr (Gln269Pro substitution caused by A→C nucleotide change at position 880) greatly reduces leptin binding at the cell surface, establishing that this single residue in the extracellular domain is critical for leptin binding and that loss of Lepr function causes the obese phenotype.\",\n      \"method\": \"PCR-based mutagenesis to introduce fa mutation into mouse Lepr cDNA; transient transfection; cell-surface leptin binding assay; genetic co-segregation analysis in 1028 meioses\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro mutagenesis + binding assay + genetic co-segregation across large cross; multiple orthogonal methods in one study\",\n      \"pmids\": [\"8690163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The long form of OB-R mediates ligand-induced activation of STAT1, STAT3, and STAT5 and stimulates transcription via IL-6 and hematopoietin receptor responsive gene elements. Deletion and tyrosine substitution mutagenesis identified two distinct regions of the intracellular domain required for signaling. Chimeric receptor experiments showed that aggregation of two OB-R intracellular domains is sufficient for ligand-induced activation, providing evidence for receptor homo-oligomerization.\",\n      \"method\": \"Cytoplasmic domain deletion and tyrosine substitution mutagenesis; G-CSF receptor/OB-R chimera signaling assays; STAT activation reporter assays; dominant negative repression experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis combined with chimeric receptor reconstitution and multiple signaling readouts in one study\",\n      \"pmids\": [\"9020115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"OB-R undergoes spontaneous homo-oligomerization (demonstrated by co-immunoprecipitation of two differently epitope-tagged OB-R molecules), and leptin signaling does not require interaction with gp130 or LIFR, as leptin stimulation does not induce tyrosine phosphorylation of gp130 or LIFR.\",\n      \"method\": \"Co-immunoprecipitation of differentially epitope-tagged OB-R constructs; tyrosine phosphorylation assays; Ba/F3 cell transfection and proliferation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with tagged constructs plus functional signaling assays; independently consistent with White et al. 1997\",\n      \"pmids\": [\"9038364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Stimulation of the long form of OB-R leads to STAT3 tyrosine phosphorylation and p42ERK2 activation, but unlike gp130, OB-R long form does not induce tyrosine phosphorylation of the SHP-2 phosphatase. The truncated short form of OB-R expressed in db/db mice fails to activate STAT3, establishing that the long intracellular domain is required for STAT3 signaling.\",\n      \"method\": \"Tyrosine phosphorylation assays; STAT3 immunoprecipitation; ERK activation assays; comparison of long vs. truncated OB-R isoforms\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct comparison of receptor isoforms with multiple signaling pathway readouts; consistent with White et al. 1997\",\n      \"pmids\": [\"9003804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The long splice variant of the leptin receptor (Ob-Rb) is expressed in hindbrain neuronal regions including the nucleus of the solitary tract, lateral parabrachial nucleus, and medullary reticular nucleus, while short receptor splice variants are abundantly expressed in leptomeninges and choroid plexus, establishing anatomical segregation of functional isoforms in the rodent brain.\",\n      \"method\": \"In situ hybridization with isoform-specific probes in mouse and rat hindbrain\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by in situ hybridization with isoform discrimination; single lab but clear isoform-specific pattern\",\n      \"pmids\": [\"9421394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LEPR-mediated feedback regulation of leptin (Lep) mRNA expression in brown adipose tissue (BAT) operates primarily through CNS-mediated effects on sympathetic nervous system (SNS) activity, whereas leptin expression in white adipose tissue (WAT) is regulated through mechanisms not directly dependent on SNS activity. Metabolic rate (SNS surrogate) explained 87% of variation in BAT-Lep mRNA.\",\n      \"method\": \"Genetic segregation of Lepr(fa) allele in rat pups; artificial rearing under thermoneutral conditions; oral norepinephrine administration; quantitative Lep mRNA measurement in BAT and WAT; plasma leptin measurement\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetically controlled experimental system with multiple manipulations and quantitative molecular readouts; single lab\",\n      \"pmids\": [\"11160998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIF-1α directly activates leptin receptor (Ob-R) transcription by binding to a hypoxia-responsive element (HRE) at -828/-832 in the Ob-R gene promoter in pancreatic cancer cells. HIF-1α silencing reduces Ob-R expression both in vitro and in xenograft models.\",\n      \"method\": \"HIF-1α overexpression and siRNA knockdown; chromatin immunoprecipitation (ChIP) for HRE binding; xenograft mouse models with HIF-1α inhibition; immunohistochemistry\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus loss-of-function in vitro and in vivo; single lab\",\n      \"pmids\": [\"25130171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LepR-mediated transport of leptin across brain barriers (endothelial and choroid plexus epithelial cells) controls food reward but is not required for homeostatic feeding control. Selective deletion of LepR in brain endothelial and epithelial cells caused hyperphagia and increased sensitivity to food reward on high-fat diet, while leaving median eminence and tanycyte LepR expression intact.\",\n      \"method\": \"Conditional LepR knockout in brain endothelial/epithelial cells (LepRbeKO mice); perfusion studies measuring brain leptin uptake; behavioral testing on high-fat diet; body weight and food intake measurements\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with brain uptake perfusion studies and behavioral phenotyping; multiple orthogonal readouts\",\n      \"pmids\": [\"29254602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hypothalamic tanycytes express functional LepR that responds to leptin by triggering Ca2+ waves and target protein phosphorylation. Tanycytic transcytotic transport of leptin into the brain requires activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, causing increased food intake, lipogenesis, and glucose intolerance through attenuated insulin secretion by pancreatic β-cells.\",\n      \"method\": \"Multiple complementary mouse models with selective LepR deletion in tanycytes; Ca2+ imaging; protein phosphorylation assays; leptin transport measurement; metabolic phenotyping; insulin secretion assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary genetic models, Ca2+ signaling assays, transport measurements, and metabolic phenotyping; multiple orthogonal methods\",\n      \"pmids\": [\"34341568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A GABAergic population of hypothalamic LepRb neurons co-expressing Glp1r (LepRbGlp1r neurons) plays a crucial role in suppression of food intake by leptin. Ablating Lepr from LepRbGlp1r neurons provoked hyperphagic obesity without impairing energy expenditure. Restoration of Lepr in GABAergic neurons required Lepr expression in Glp1r-expressing neurons to improve energy balance.\",\n      \"method\": \"Single-nucleus RNA-seq of enriched hypothalamic LepRb cells; cell-type-specific Lepr ablation; Lepr reactivation in otherwise Lepr-null mice; body weight and food intake measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-nucleus RNA-seq identification combined with conditional KO and rescue genetic epistasis experiments with defined phenotypic readouts\",\n      \"pmids\": [\"37581939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A subpopulation of lateral hypothalamic GABAergic LEPR-expressing neurons (LHLEPR) specifically drives appetitive but not consummatory behaviors. Ablation of LHLEPR neurons prevented appetitive learning in Pavlovian conditioning but did not affect feeding. LHLEPR→VTA projections bidirectionally modulate reward-related behaviors, and chemogenetic inhibition of LHLEPR neurons attenuates cocaine sensitization but not cocaine conditioned place preference.\",\n      \"method\": \"Neuron-specific ablation; Pavlovian conditioning paradigm; optogenetic activation/inhibition; chemogenetic (DREADD) manipulation; food intake and weight measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type specific ablation, optogenetics, and chemogenetics with multiple behavioral paradigms identifying circuit-level function\",\n      \"pmids\": [\"34433027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Leptin binding to OB-R inhibits leptin transport across a human in vitro BBB model (hCMEC/D3 cells) — specifically, an OB-R-neutralizing antibody that blocks leptin-OB-R binding and STAT3 phosphorylation does NOT inhibit leptin transcytosis, establishing that OB-R signaling is not required for leptin transport across human endothelial cells. LRP-2 (megalin) is expressed in these cells and may serve as the primary leptin transporter.\",\n      \"method\": \"In vitro human BBB model (hCMEC/D3); OB-R neutralizing antibody (9F8) treatment; STAT3 phosphorylation assay; transcytosis/transport measurement; endocytosis inhibitor assays; LRP-2 expression analysis\",\n      \"journal\": \"Journal of neuroendocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional inhibition of OB-R with validated antibody plus transport measurements; negative result about OB-R transport role is well-controlled\",\n      \"pmids\": [\"27037668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LepR mutation replacing the three intracellular tyrosine residues (Tyr985, Tyr1077, Tyr1138) with phenylalanine (Y123F mice) causes follicle loss and infertility in female mice, associated with elevated phosphorylation of Akt, mTOR, S6K1, and eIF4B (PTEN/PI3K/mTOR pathway activation) in ovaries, establishing that LepR tyrosine signaling normally suppresses the PTEN/PI3K/mTOR pathway in ovarian follicles.\",\n      \"method\": \"Homologous gene targeting to generate Y123F mice; reproductive phenotyping; AMH measurement; follicle counting; western blotting for pathway components\",\n      \"journal\": \"Gynecological endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted mutagenesis of specific tyrosine residues with molecular pathway analysis; single lab\",\n      \"pmids\": [\"30145913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LEPR interacts with ANXA7 (Annexin A7) in hepatocellular carcinoma cells (co-immunoprecipitation), and mechanistically LEPR regulates ERK1/2 and JAK2/STAT3 signaling via ANXA7.\",\n      \"method\": \"Co-immunoprecipitation; western blotting; immunofluorescence; functional assays (proliferation, migration, invasion, apoptosis); siRNA knockdown\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction; mechanistic downstream pathway inferred from knockdown experiments without reconstitution; single lab\",\n      \"pmids\": [\"33397392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Leptin/obR signaling promotes M1 macrophage polarization via phosphorylation of the long isoform of obR and activation of JNK/STAT3/AKT signaling pathways; leptin-mediated M1 macrophage activity increases CXCL2 production and neutrophil recruitment in obesity-related airway inflammation.\",\n      \"method\": \"db/db obR-deficient mice; obR blockade (Allo-Aca); bone marrow-derived macrophage (BMDM) in vitro experiments; flow cytometry; western blotting; ELISA; BALF cytokine analysis\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deficiency model combined with pharmacological blockade and in vitro mechanistic experiments; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"37488474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GABAergic LepRGlp1r neurons in the dorsomedial hypothalamus (DMH) mediate suppression of food intake and body weight by a GLP-1R/LepR dual agonist. Ablating Lepr in Glp1r-expressing neurons abrogated the dual agonist's food intake suppression. Reactivation of Glp1r in Lepr neurons on an otherwise Glp1r-null background was sufficient to restore dual agonist efficacy. LepRGlp1r neurons exist in non-human primate DMH.\",\n      \"method\": \"Conditional Lepr ablation in Glp1r neurons; Glp1r reactivation in Lepr neurons; pharmacological dual agonist treatment; food intake and body weight measurement; immunohistochemistry in NHP\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and genetic rescue (reactivation) provide bidirectional epistasis evidence for circuit-level mechanism; translational validation in NHP\",\n      \"pmids\": [\"39630884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GIPR and Lepr strongly co-localize in pancreatic β-cells but not in hypothalamus or hindbrain. Loss of GIPR in Lepr-expressing cells abolishes the superior glycemic effects of GIPR:GLP-1R co-agonism over single GLP-1R agonism, but does not affect body weight or food intake, establishing that LepR+ pancreatic cells (not brain neurons) mediate the glycemic but not anorectic actions of GIP.\",\n      \"method\": \"Single-cell RNA-seq co-expression analysis; Lepr-specific Gipr conditional knockout; metabolic phenotyping; GIP and dual agonist pharmacology in DIO mice\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with pharmacological dissection and scRNA-seq; multiple orthogonal readouts establishing tissue-specific functional role\",\n      \"pmids\": [\"38492844\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LEPR (OB-R) is a single-pass class I cytokine receptor that binds leptin and signals as a homo-oligomer; the long isoform (LepRb) activates JAK2-STAT3, MAPK/ERK, and PI3K/AKT pathways via two critical intracellular tyrosine-containing regions, whereas short isoforms lack STAT3-activating capacity; in the brain, LepRb in specific GABAergic hypothalamic neuron populations (including Glp1r-co-expressing DMH neurons) suppresses food intake and body weight, while LepR in tanycytes and blood-brain barrier cells mediates transcytotic leptin transport into the brain, and LepR in pancreatic β-cells contributes to glucose control downstream of GIP signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LEPR (OB-R) is a single membrane-spanning class I cytokine receptor, structurally related to gp130 and the G-CSF/LIF receptors, that serves as the principal signal-transducing receptor for leptin and thereby links peripheral energy stores to central control of food intake and metabolism [#0]. A single extracellular residue (Gln269) is critical for high-affinity leptin binding, and its loss in the rat fatty (fa) allele abolishes surface binding and produces obesity, establishing LEPR loss-of-function as causal for the obese phenotype [#1]. LEPR signals as a spontaneously formed homo-oligomer—aggregation of two intracellular domains is sufficient for activation, and signaling proceeds without recruitment of gp130 or LIFR [#2, #3]. The long isoform (Ob-Rb) activates STAT1/3/5, ERK/MAPK, and, through its intracellular tyrosine residues (Tyr985, Tyr1077, Tyr1138), the PI3K/AKT/mTOR axis, whereas truncated short isoforms expressed in db/db animals fail to activate STAT3 [#2, #4, #13]. Functional isoforms are anatomically segregated in the brain, with Ob-Rb concentrated in hindbrain neuronal nuclei and short variants in choroid plexus and leptomeninges [#5]. In the brain, leptin acts through distinct LepRb neuron populations: GABAergic dorsomedial hypothalamic neurons co-expressing Glp1r suppress food intake and body weight and mediate the efficacy of GLP-1R/LepR dual agonists [#10, #16], while a lateral hypothalamic GABAergic LEPR population drives appetitive reward behaviors via projections to the VTA [#11]. LepR additionally governs leptin entry into the brain: tanycytic transcytosis requires sequential activation of a LepR-EGFR complex, and its loss blocks leptin entry and produces hyperphagia, lipogenesis, and glucose intolerance [#9], while LepR in brain barrier endothelial/epithelial cells controls food reward distinct from homeostatic feeding [#8]. LepR+ pancreatic cells, where LepR co-localizes with GIPR, mediate the glycemic but not the anorectic actions of incretin co-agonism [#17]. Beyond CNS and metabolic roles, LepR transcription is induced by HIF-1\\u03b1 via a promoter HRE in cancer cells [#7], and leptin/OB-R signaling promotes M1 macrophage polarization through JNK/STAT3/AKT, linking it to obesity-related inflammation [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of the leptin receptor, answering what cell-surface protein transduces the leptin signal and placing it in the class I cytokine receptor family.\",\n      \"evidence\": \"expression cloning from mouse choroid plexus with a leptin-AP fusion probe and [125I]leptin binding\",\n      \"pmids\": [\"8548812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which isoform mediates intracellular signaling\", \"Binding stoichiometry and oligomeric state not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Connected receptor function to phenotype by showing a single extracellular residue governs leptin binding and that its loss causes obesity.\",\n      \"evidence\": \"introduction of the rat fa Gln269Pro mutation into Lepr cDNA, cell-surface binding assays, and co-segregation across 1028 meioses\",\n      \"pmids\": [\"8690163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full leptin-binding interface\", \"Downstream signaling consequences of binding loss not measured here\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the signaling logic of LEPR: it homo-oligomerizes independently of gp130/LIFR and uses two distinct intracellular regions to activate STATs and ERK, with the long domain required for STAT3.\",\n      \"evidence\": \"deletion/tyrosine-substitution mutagenesis, G-CSFR/OB-R chimeras, reciprocal Co-IP of tagged receptors, and STAT/ERK readouts across three studies\",\n      \"pmids\": [\"9020115\", \"9038364\", \"9003804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map individual tyrosine residues to specific outputs in vivo\", \"JAK kinase identity and recruitment not resolved in these studies\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that long and short LEPR isoforms are anatomically segregated in the brain, implying region-specific signaling versus transport roles.\",\n      \"evidence\": \"isoform-specific in situ hybridization in mouse and rat hindbrain\",\n      \"pmids\": [\"9421394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression mapping does not establish functional roles per region\", \"Single-lab localization without functional perturbation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that LEPR-dependent feedback on leptin production is CNS-routed via the sympathetic nervous system in brown but not white fat, framing LEPR within a closed-loop energy-balance circuit.\",\n      \"evidence\": \"fa-allele segregation in rat pups, thermoneutral artificial rearing, norepinephrine administration, and Lep mRNA quantification\",\n      \"pmids\": [\"11160998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WAT regulatory mechanism left undefined\", \"Indirect inference of SNS activity from metabolic rate\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissociated leptin transport from OB-R signaling at the human BBB, showing OB-R signaling is dispensable for transcytosis and implicating LRP-2/megalin instead.\",\n      \"evidence\": \"human hCMEC/D3 BBB model with OB-R-neutralizing antibody, STAT3 phosphorylation, and transcytosis assays\",\n      \"pmids\": [\"27037668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly prove LRP-2 mediates transport\", \"In vitro human model may differ from rodent barrier biology\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a transcriptional input to LEPR by showing HIF-1\\u03b1 directly drives Ob-R promoter activity in cancer cells.\",\n      \"evidence\": \"HIF-1\\u03b1 overexpression/knockdown, ChIP at the -828/-832 HRE, and xenograft models\",\n      \"pmids\": [\"25130171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of HIF-driven LEPR in tumor biology not fully defined\", \"Single-lab finding restricted to pancreatic cancer cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed brain-barrier LepR controls leptin transport governing food reward, separating this function from homeostatic feeding control.\",\n      \"evidence\": \"endothelial/epithelial-specific LepR knockout, brain leptin uptake perfusion, and high-fat-diet behavioral testing\",\n      \"pmids\": [\"29254602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular transport machinery downstream of LepR not defined\", \"Reward circuitry linkage inferred behaviorally\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined tanycytic LepR as a leptin-responsive, transport-gating receptor requiring a sequential LepR-EGFR complex, controlling both brain leptin entry and systemic glucose handling.\",\n      \"evidence\": \"multiple tanycyte-specific LepR deletion models, Ca2+ imaging, phosphorylation assays, transport measurement, and metabolic/insulin-secretion phenotyping\",\n      \"pmids\": [\"34341568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular coupling between LepR and EGFR not structurally resolved\", \"Relationship to barrier-cell transport pathway not reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved hypothalamic LepRb circuitry into functionally distinct GABAergic populations: Glp1r-co-expressing neurons suppress feeding, while lateral hypothalamic LEPR neurons drive appetitive reward.\",\n      \"evidence\": \"single-nucleus RNA-seq, cell-type-specific ablation/reactivation, optogenetics, chemogenetics, and behavioral paradigms across two studies\",\n      \"pmids\": [\"37581939\", \"34433027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling distinguishing these populations not defined\", \"Connectivity between feeding and reward LepR populations unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Assigned a reproductive function to LEPR tyrosine signaling, showing the three intracellular tyrosines normally restrain the PI3K/mTOR pathway in ovarian follicles.\",\n      \"evidence\": \"Y123F (Tyr985/1077/1138-to-Phe) knock-in mice with follicle counting and pathway western blotting\",\n      \"pmids\": [\"30145913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cannot attribute the phenotype to a single tyrosine residue\", \"Cell-autonomous versus systemic contribution to infertility not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended LEPR function to immunity, showing leptin/OB-R signaling drives M1 macrophage polarization and neutrophil recruitment in obesity-related airway inflammation.\",\n      \"evidence\": \"db/db obR-deficient mice, pharmacological obR blockade, and BMDM in vitro signaling/cytokine assays\",\n      \"pmids\": [\"37488474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus systemic effects of obR loss not fully separated\", \"Single-lab finding within a specific inflammation context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed the tissue sites of incretin co-agonist action relative to LepR: DMH GABAergic LepRGlp1r neurons mediate anorexia, while LepR+ pancreatic cells expressing GIPR mediate the glycemic benefit.\",\n      \"evidence\": \"conditional Lepr/Gipr knockouts and Glp1r reactivation, scRNA-seq co-expression, dual-agonist pharmacology, and NHP immunohistochemistry across two studies\",\n      \"pmids\": [\"39630884\", \"38492844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling crosstalk between LepR and GIPR/GLP-1R in the same cells not defined\", \"Pancreatic LepR's own ligand-dependent role not isolated from GIPR effects\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LEPR signaling outputs are differentially wired across the distinct neuronal, glial, barrier, pancreatic, and immune cell types to produce tissue-specific physiology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the ligand-bound oligomeric receptor in the corpus\", \"Mechanism coupling LepR to EGFR and to incretin receptors not defined\", \"How identical intracellular tyrosines yield divergent outcomes across tissues is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9, 17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 10, 11, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\n      \"LEPR homo-oligomer\",\n      \"LepR-EGFR complex\"\n    ],\n    \"partners\": [\n      \"LEP\",\n      \"EGFR\",\n      \"GIPR\",\n      \"ANXA7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}