{"gene":"LEP","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"Leptin (LEP gene product) exerts tissue-specific negative autoregulation: moderate increases in circulating leptin decreased Lep expression in adipose tissue and induced Lep expression in skeletal muscle (a tissue that normally does not express the gene), demonstrating cross-talk between adipose tissue and skeletal muscle via leptin secretion.","method":"In vivo leptin administration with tissue-specific mRNA measurements (Northern/RT-PCR) in rodents; nutritional manipulation experiments","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo intervention with tissue-specific gene expression readouts, single lab, two orthogonal approaches (leptin infusion and nutritional regulation)","pmids":["10426312"],"is_preprint":false},{"year":1998,"finding":"Insulin is required for food intake-dependent increases in Lep mRNA and plasma leptin: in streptozotocin-treated (insulin-deficient) animals, changes in food intake (fasting or feeding) did not alter plasma insulin and consequently failed to alter Lep mRNA or plasma leptin, establishing insulin as a necessary mediator of nutritional regulation of Lep expression in adipose tissue.","method":"Streptozotocin-induced insulin deficiency in rats with measurements of Lep mRNA (Northern blot) and plasma leptin/insulin under fasting and feeding conditions","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological loss-of-function model with specific molecular readout, single lab, two orthogonal measurements (mRNA and protein)","pmids":["9591754"],"is_preprint":false},{"year":1998,"finding":"Heterozygosity at Lep(ob) reduces leptin protein produced per unit fat mass, and body fat accumulates in Lep(ob)/+ mice until plasma leptin reaches the level of wild-type mice, consistent with a fat-mass set-point regulated by leptin concentration. Additionally, elevated plasma leptin in Lep(rdb)/+ mice suggests that the leptin receptor (LEPR) mediates autocrine suppression of Lep expression.","method":"Body composition analysis and plasma leptin measurements in +/+, Lep(ob)/+, Lep(rdb)/+, and compound heterozygous mice; gene dosage comparison","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with quantitative physiological readouts, single lab, gene-dosage and receptor-genotype comparison","pmids":["9575960"],"is_preprint":false},{"year":2000,"finding":"Dopamine signaling is required downstream of leptin deficiency for hyperphagia: leptin-null (Lep(ob/ob)) mice that also lack dopamine (DD x Lep(ob/ob) double mutants) failed to feed when L-DOPA treatment was withdrawn despite retained locomotor capacity, demonstrating that dopamine is necessary for the feeding behavior driven by leptin deficiency.","method":"Genetic epistasis — double mutant mice (dopamine-deficient x Lep(ob/ob)) with L-DOPA rescue and behavioral feeding assessment","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with specific behavioral readout, demonstrated that dopamine is required for feeding in leptin-null context, rigorous pharmacological rescue (L-DOPA) confirming interpretation","pmids":["10802666"],"is_preprint":false},{"year":2002,"finding":"SREBP-1 is required for leptin-deficiency-induced fatty liver but not for obesity or insulin resistance: Lep(ob/ob) x Srebp-1(-/-) double-mutant mice showed marked attenuation of hepatic triglyceride accumulation and reduced lipogenic enzyme mRNAs in liver, but remained obese and insulin resistant, placing SREBP-1 downstream of leptin deficiency specifically in the hepatic lipogenesis pathway.","method":"Genetic epistasis — double-knockout mice (Lep(ob/ob) x Srebp-1(-/-)) with hepatic lipid analysis, mRNA quantification of lipogenic enzymes, and metabolic phenotyping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double-knockout epistasis with multiple orthogonal readouts (lipid quantification, gene expression, metabolic phenotype), dissecting hepatic from adipose and whole-body effects","pmids":["11923308"],"is_preprint":false},{"year":2004,"finding":"Hormone-sensitive lipase (HSL) is required for full adipogenesis in leptin-deficient mice: Lep(ob/ob)/HSL(-/-) double mutants showed reduced food intake, weight gain, and adiposity compared to Lep(ob/ob)/HSL(+/+) mice, with accumulation of preadipocytes and decreased expression of mature adipocyte marker genes. Hypothalamic NPY and AgRP expression was decreased, suggesting that HSL in the hypothalamus generates free fatty acids that modulate orexigenic neuropeptide expression in the context of leptin deficiency.","method":"Genetic epistasis — double-knockout mice (Lep(ob/ob) x HSL(-/-)) with body composition, adipose tissue histology, gene expression analysis of adipocyte differentiation markers and hypothalamic neuropeptides","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple tissue-specific molecular readouts, single lab, pathway placement of HSL relative to leptin deficiency","pmids":["14752112"],"is_preprint":false},{"year":2016,"finding":"Hyperinsulinemia is required for excess adiposity in leptin-deficient Lep(ob/ob) mice: reducing insulin gene dosage by 2–3 alleles in Lep(ob/ob) mice reduced plasma insulin by 75–95% and attenuated body weight gain by 50–90%, with ~30–50% reduced total body fat, placing excess insulin as a necessary downstream mediator of leptin-deficiency-induced obesity.","method":"Genetic epistasis — Lep(ob/ob) mice crossed with graded insulin gene knockouts (Ins1/Ins2 allele series); body composition, glucose homeostasis, and islet morphology assessed","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — graded genetic insulin reduction with dose-response in Lep(ob/ob) background, multiple orthogonal phenotypic readouts (body weight, fat mass, glycemia, islet morphology), mechanistically establishes insulin as mediator of leptin-deficiency obesity","pmids":["27818936"],"is_preprint":false},{"year":2021,"finding":"miR-874-3p directly targets the LEP 3'UTR to suppress LEP expression and promote osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs): luciferase reporter and RNA pull-down assays confirmed LEP as a direct target; overexpression of LEP reversed miR-874-3p-induced osteoblast marker expression, calcium deposition, and cell proliferation.","method":"Luciferase reporter assay and RNA pull-down to validate miR-874-3p–LEP targeting; gain-of-function and rescue experiments in hBMSCs with osteogenic differentiation markers (ALP, RUNX2, OCN, OSX) and alizarin red staining","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by two orthogonal methods (luciferase + RNA pull-down) plus functional rescue, single lab","pmids":["34818977"],"is_preprint":false},{"year":2009,"finding":"Common SNP variants in the LEP locus are major determinants of basal leptin expression in peripheral blood mononuclear cells, and the same LEP variants that associate with leptin expression also associate with a 1.7–2-fold higher level of LPS-induced IL-6 expression; basal leptin expression significantly correlates with LPS-induced IL-6 expression, placing LEP/leptin as a trans-acting regulator of IL-6 induction in immune cells.","method":"Expression and protein quantitative trait locus mapping in PBMCs with high-density SNP typing; correlation of leptin expression levels with LPS-induced IL-6 expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — eQTL approach with correlation of leptin and IL-6 expression levels, single lab but used both protein and expression QTL readouts; mechanistic link is correlative rather than interventional","pmids":["19942621"],"is_preprint":false},{"year":1996,"finding":"The porcine obesity gene (OBS/LEP) ortholog was physically mapped to pig chromosome 18 by PCR of somatic cell hybrids, and partial cDNA sequence showed 86% identity to human and 84% identity to mouse LEP cDNA, confirming conservation of the gene across mammals.","method":"RT-PCR from pig white adipose tissue, sequencing, and somatic cell hybrid PCR mapping","journal":"Animal genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and physical mapping with sequence identity confirmation, single lab","pmids":["8856925"],"is_preprint":false},{"year":2013,"finding":"FABP4 knockdown in bovine adipocytes significantly decreased LEP and ADIPOQ mRNA expression (without affecting preadipocyte differentiation genes), indicating that FABP4 positively regulates LEP expression in adipocytes as part of lipid metabolism regulation.","method":"Adenovirus-mediated shRNA knockdown of FABP4 in bovine adipocytes; RT-PCR quantification of LEP, ADIPOQ, and LEPR mRNA at 24 h and 72 h","journal":"Genetics and molecular research : GMR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (mRNA measurement after knockdown), indirect regulatory relationship, bovine primary cells","pmids":["23315880"],"is_preprint":false}],"current_model":"LEP encodes leptin, a hormone secreted by white adipose tissue that regulates energy homeostasis through multiple mechanisms: it exerts tissue-specific negative autoregulation of its own expression in fat (and induces expression in skeletal muscle), requires insulin as a necessary mediator for nutritional upregulation, acts upstream of dopamine signaling for hyperphagia, and operates through SREBP-1 to drive hepatic lipogenesis while being dispensable for adiposity per se; downstream of leptin deficiency, hyperinsulinemia is a required mediator of excess adiposity, and leptin/LEP variants also modulate IL-6 production in immune cells and osteogenic differentiation via miR-874-3p targeting of the LEP 3'UTR."},"narrative":{"mechanistic_narrative":"LEP encodes leptin, a hormone secreted by white adipose tissue that operates as a central regulator of energy homeostasis, acting both on its own expression and on multiple downstream effector pathways [PMID:10426312, PMID:9575960]. Leptin exerts tissue-specific negative autoregulation, suppressing its own expression in adipose tissue while inducing expression in skeletal muscle, establishing inter-tissue cross-talk via the circulating hormone [PMID:10426312]; gene-dosage and receptor-genotype experiments place this autocrine suppression downstream of the leptin receptor and indicate that fat mass accumulates toward a set-point defined by leptin concentration [PMID:9575960]. Nutritional regulation of LEP expression in adipose tissue requires insulin as a necessary mediator [PMID:9591754]. Genetic epistasis in leptin-deficient (Lep(ob/ob)) mice resolves distinct downstream branches of leptin action: dopamine signaling is required for the hyperphagia of leptin deficiency [PMID:10802666], SREBP-1 mediates leptin-deficiency-induced hepatic lipogenesis but is dispensable for obesity and insulin resistance [PMID:11923308], hormone-sensitive lipase is needed for full adipogenesis and modulates hypothalamic orexigenic neuropeptide expression [PMID:14752112], and hyperinsulinemia is a required mediator of excess adiposity [PMID:27818936]. Beyond energy balance, LEP expression is directly suppressed by miR-874-3p binding to its 3'UTR, a regulatory axis that controls osteogenic differentiation of human bone marrow mesenchymal stem cells [PMID:34818977], and LEP locus variants act as a trans-acting determinant of LPS-induced IL-6 expression in immune cells [PMID:19942621].","teleology":[{"year":1996,"claim":"Established that LEP is an evolutionarily conserved adipose-expressed gene, providing the molecular foundation for cross-species study of its product.","evidence":"RT-PCR cloning, sequencing, and somatic cell hybrid mapping of the porcine OBS/LEP ortholog","pmids":["8856925"],"confidence":"Medium","gaps":["Sequence conservation does not establish functional equivalence","No functional assay of the cloned product"]},{"year":1998,"claim":"Resolved that nutritional regulation of LEP expression is not direct but requires insulin as a necessary upstream mediator.","evidence":"Streptozotocin-induced insulin deficiency in rats with Lep mRNA and plasma leptin/insulin readouts under fasting and feeding","pmids":["9591754"],"confidence":"Medium","gaps":["Does not define the insulin signaling intermediates in adipocytes","Pharmacological model may have pleiotropic effects beyond insulin loss"]},{"year":1998,"claim":"Showed that fat mass is regulated toward a set-point defined by leptin concentration and that the leptin receptor mediates autocrine suppression of LEP.","evidence":"Body composition and plasma leptin measurements in Lep(ob)/+ and Lep(rdb)/+ gene-dosage/receptor-genotype mouse comparisons","pmids":["9575960"],"confidence":"Medium","gaps":["Receptor-mediated suppression inferred from genotype correlation, not direct intervention","Molecular mechanism of autocrine feedback unresolved"]},{"year":1999,"claim":"Demonstrated tissue-specific negative autoregulation of LEP and leptin-mediated adipose–muscle cross-talk, refining how leptin shapes its own expression landscape.","evidence":"In vivo leptin administration and nutritional manipulation in rodents with tissue-specific mRNA measurement","pmids":["10426312"],"confidence":"Medium","gaps":["Transcriptional machinery driving opposite tissue responses unknown","Physiological role of muscle LEP induction undefined"]},{"year":2000,"claim":"Placed dopamine signaling as a required downstream node for the hyperphagia caused by leptin deficiency, linking leptin to a defined neurotransmitter pathway.","evidence":"Genetic epistasis with dopamine-deficient x Lep(ob/ob) double mutants and L-DOPA rescue of feeding behavior","pmids":["10802666"],"confidence":"High","gaps":["Circuit-level site of dopamine action not mapped","Does not address dopamine's role in body-weight set-point versus acute feeding"]},{"year":2002,"claim":"Dissected leptin-deficiency phenotypes by showing SREBP-1 drives hepatic lipogenesis but is dispensable for obesity and insulin resistance, separating fatty liver from whole-body metabolic disease.","evidence":"Lep(ob/ob) x Srebp-1(-/-) double-knockout with hepatic lipid quantification, lipogenic enzyme mRNA, and metabolic phenotyping","pmids":["11923308"],"confidence":"High","gaps":["Does not identify the signal linking leptin deficiency to hepatic SREBP-1 activation","Residual hepatic lipid pathways not characterized"]},{"year":2004,"claim":"Identified hormone-sensitive lipase as required for full adipogenesis in leptin deficiency and proposed an HSL-derived fatty acid signal modulating hypothalamic orexigenic neuropeptides.","evidence":"Lep(ob/ob) x HSL(-/-) double-knockout with body composition, adipose histology, and hypothalamic NPY/AgRP expression","pmids":["14752112"],"confidence":"Medium","gaps":["Free-fatty-acid signal to hypothalamus is inferred, not directly demonstrated","Cell-autonomous versus systemic role of HSL not separated"]},{"year":2009,"claim":"Connected LEP genetic variation to immune function, identifying leptin expression as a trans-acting correlate of LPS-induced IL-6 in immune cells.","evidence":"Expression and protein QTL mapping in PBMCs with high-density SNP typing and correlation with LPS-induced IL-6","pmids":["19942621"],"confidence":"Medium","gaps":["Link is correlative rather than interventional","Causal mechanism connecting leptin levels to IL-6 induction undefined"]},{"year":2016,"claim":"Established hyperinsulinemia as a necessary downstream mediator of leptin-deficiency-induced obesity, repositioning excess insulin as cause rather than consequence of adiposity.","evidence":"Graded insulin gene knockout (Ins1/Ins2 allele series) in Lep(ob/ob) mice with body composition, glycemia, and islet morphology","pmids":["27818936"],"confidence":"High","gaps":["Does not define the tissues where reduced insulin limits fat accrual","Relationship to leptin's central versus peripheral actions unresolved"]},{"year":2021,"claim":"Defined a post-transcriptional control of LEP via direct miR-874-3p targeting of its 3'UTR that governs osteogenic differentiation, extending LEP regulation beyond metabolism.","evidence":"Luciferase reporter and RNA pull-down validation plus gain-of-function/rescue in human BMSCs with osteoblast markers and mineralization assays","pmids":["34818977"],"confidence":"Medium","gaps":["In vivo relevance to bone formation not tested","Downstream effectors linking LEP to osteogenic markers not mapped"]},{"year":null,"claim":"The molecular signaling intermediates that integrate leptin's autoregulation, insulin dependence, and tissue-specific downstream branches (dopamine, SREBP-1, HSL, insulin) into a unified mechanism remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct receptor-to-effector signaling chain established in the corpus","Human in vivo validation of the rodent epistasis findings is absent","Mechanism coupling leptin status to hepatic SREBP-1 and hypothalamic neuropeptides not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7]}],"complexes":[],"partners":["LEPR","INS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41159","full_name":"Leptin","aliases":["Obese protein","Obesity factor"],"length_aa":167,"mass_kda":18.6,"function":"Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:15899045, PubMed:17344214, PubMed:19688109). In the hypothalamus, 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. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689, PubMed:8589726). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 which promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P41159/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LEP","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LEP","total_profiled":1310},"omim":[{"mim_id":"621223","title":"ALLOGRAFT INFLAMMATORY FACTOR 1-LIKE PROTEIN; AIF1L","url":"https://www.omim.org/entry/621223"},{"mim_id":"621052","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN N1; PLEKHN1","url":"https://www.omim.org/entry/621052"},{"mim_id":"619392","title":"CHROMOSOME 14 OPEN READING FRAME 180; C14ORF180","url":"https://www.omim.org/entry/619392"},{"mim_id":"618081","title":"IMMUNOGLOBULIN-LIKE DOMAIN-CONTAINING RECEPTOR 2; ILDR2","url":"https://www.omim.org/entry/618081"},{"mim_id":"617869","title":"NK1 HOMEOBOX 1; NKX1-1","url":"https://www.omim.org/entry/617869"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":288.5},{"tissue":"breast","ntpm":88.4}],"url":"https://www.proteinatlas.org/search/LEP"},"hgnc":{"alias_symbol":[],"prev_symbol":["OBS","OB"]},"alphafold":{"accession":"P41159","domains":[{"cath_id":"1.20.1250.10","chopping":"22-162","consensus_level":"high","plddt":82.1693,"start":22,"end":162}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41159","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41159-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41159-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LEP","jax_strain_url":"https://www.jax.org/strain/search?query=LEP"},"sequence":{"accession":"P41159","fasta_url":"https://rest.uniprot.org/uniprotkb/P41159.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41159/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41159"}},"corpus_meta":[{"pmid":"11923308","id":"PMC_11923308","title":"Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11923308","citation_count":297,"is_preprint":false},{"pmid":"10802666","id":"PMC_10802666","title":"Dopamine is required for hyperphagia in Lep(ob/ob) mice.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10802666","citation_count":115,"is_preprint":false},{"pmid":"20930547","id":"PMC_20930547","title":"DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age.","date":"2011","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20930547","citation_count":102,"is_preprint":false},{"pmid":"27777020","id":"PMC_27777020","title":"Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).","date":"2016","source":"The Lancet. Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27777020","citation_count":100,"is_preprint":false},{"pmid":"22526452","id":"PMC_22526452","title":"Fetal growth restriction: current knowledge to the general Obs/Gyn.","date":"2012","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/22526452","citation_count":87,"is_preprint":false},{"pmid":"31146162","id":"PMC_31146162","title":"Bioaccumulation in the gut and liver causes gut barrier dysfunction and hepatic metabolism disorder in mice after exposure to low doses of OBS.","date":"2019","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/31146162","citation_count":81,"is_preprint":false},{"pmid":"9575960","id":"PMC_9575960","title":"Heterozygosity for Lep(ob) or Lep(rdb) affects body composition and leptin homeostasis in adult mice.","date":"1998","source":"The American journal of 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tissue-specific negative autoregulation: moderate increases in circulating leptin decreased Lep expression in adipose tissue and induced Lep expression in skeletal muscle (a tissue that normally does not express the gene), demonstrating cross-talk between adipose tissue and skeletal muscle via leptin secretion.\",\n      \"method\": \"In vivo leptin administration with tissue-specific mRNA measurements (Northern/RT-PCR) in rodents; nutritional manipulation experiments\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo intervention with tissue-specific gene expression readouts, single lab, two orthogonal approaches (leptin infusion and nutritional regulation)\",\n      \"pmids\": [\"10426312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Insulin is required for food intake-dependent increases in Lep mRNA and plasma leptin: in streptozotocin-treated (insulin-deficient) animals, changes in food intake (fasting or feeding) did not alter plasma insulin and consequently failed to alter Lep mRNA or plasma leptin, establishing insulin as a necessary mediator of nutritional regulation of Lep expression in adipose tissue.\",\n      \"method\": \"Streptozotocin-induced insulin deficiency in rats with measurements of Lep mRNA (Northern blot) and plasma leptin/insulin under fasting and feeding conditions\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological loss-of-function model with specific molecular readout, single lab, two orthogonal measurements (mRNA and protein)\",\n      \"pmids\": [\"9591754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Heterozygosity at Lep(ob) reduces leptin protein produced per unit fat mass, and body fat accumulates in Lep(ob)/+ mice until plasma leptin reaches the level of wild-type mice, consistent with a fat-mass set-point regulated by leptin concentration. Additionally, elevated plasma leptin in Lep(rdb)/+ mice suggests that the leptin receptor (LEPR) mediates autocrine suppression of Lep expression.\",\n      \"method\": \"Body composition analysis and plasma leptin measurements in +/+, Lep(ob)/+, Lep(rdb)/+, and compound heterozygous mice; gene dosage comparison\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with quantitative physiological readouts, single lab, gene-dosage and receptor-genotype comparison\",\n      \"pmids\": [\"9575960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Dopamine signaling is required downstream of leptin deficiency for hyperphagia: leptin-null (Lep(ob/ob)) mice that also lack dopamine (DD x Lep(ob/ob) double mutants) failed to feed when L-DOPA treatment was withdrawn despite retained locomotor capacity, demonstrating that dopamine is necessary for the feeding behavior driven by leptin deficiency.\",\n      \"method\": \"Genetic epistasis — double mutant mice (dopamine-deficient x Lep(ob/ob)) with L-DOPA rescue and behavioral feeding assessment\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with specific behavioral readout, demonstrated that dopamine is required for feeding in leptin-null context, rigorous pharmacological rescue (L-DOPA) confirming interpretation\",\n      \"pmids\": [\"10802666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SREBP-1 is required for leptin-deficiency-induced fatty liver but not for obesity or insulin resistance: Lep(ob/ob) x Srebp-1(-/-) double-mutant mice showed marked attenuation of hepatic triglyceride accumulation and reduced lipogenic enzyme mRNAs in liver, but remained obese and insulin resistant, placing SREBP-1 downstream of leptin deficiency specifically in the hepatic lipogenesis pathway.\",\n      \"method\": \"Genetic epistasis — double-knockout mice (Lep(ob/ob) x Srebp-1(-/-)) with hepatic lipid analysis, mRNA quantification of lipogenic enzymes, and metabolic phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double-knockout epistasis with multiple orthogonal readouts (lipid quantification, gene expression, metabolic phenotype), dissecting hepatic from adipose and whole-body effects\",\n      \"pmids\": [\"11923308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hormone-sensitive lipase (HSL) is required for full adipogenesis in leptin-deficient mice: Lep(ob/ob)/HSL(-/-) double mutants showed reduced food intake, weight gain, and adiposity compared to Lep(ob/ob)/HSL(+/+) mice, with accumulation of preadipocytes and decreased expression of mature adipocyte marker genes. Hypothalamic NPY and AgRP expression was decreased, suggesting that HSL in the hypothalamus generates free fatty acids that modulate orexigenic neuropeptide expression in the context of leptin deficiency.\",\n      \"method\": \"Genetic epistasis — double-knockout mice (Lep(ob/ob) x HSL(-/-)) with body composition, adipose tissue histology, gene expression analysis of adipocyte differentiation markers and hypothalamic neuropeptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple tissue-specific molecular readouts, single lab, pathway placement of HSL relative to leptin deficiency\",\n      \"pmids\": [\"14752112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hyperinsulinemia is required for excess adiposity in leptin-deficient Lep(ob/ob) mice: reducing insulin gene dosage by 2–3 alleles in Lep(ob/ob) mice reduced plasma insulin by 75–95% and attenuated body weight gain by 50–90%, with ~30–50% reduced total body fat, placing excess insulin as a necessary downstream mediator of leptin-deficiency-induced obesity.\",\n      \"method\": \"Genetic epistasis — Lep(ob/ob) mice crossed with graded insulin gene knockouts (Ins1/Ins2 allele series); body composition, glucose homeostasis, and islet morphology assessed\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — graded genetic insulin reduction with dose-response in Lep(ob/ob) background, multiple orthogonal phenotypic readouts (body weight, fat mass, glycemia, islet morphology), mechanistically establishes insulin as mediator of leptin-deficiency obesity\",\n      \"pmids\": [\"27818936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-874-3p directly targets the LEP 3'UTR to suppress LEP expression and promote osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs): luciferase reporter and RNA pull-down assays confirmed LEP as a direct target; overexpression of LEP reversed miR-874-3p-induced osteoblast marker expression, calcium deposition, and cell proliferation.\",\n      \"method\": \"Luciferase reporter assay and RNA pull-down to validate miR-874-3p–LEP targeting; gain-of-function and rescue experiments in hBMSCs with osteogenic differentiation markers (ALP, RUNX2, OCN, OSX) and alizarin red staining\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by two orthogonal methods (luciferase + RNA pull-down) plus functional rescue, single lab\",\n      \"pmids\": [\"34818977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Common SNP variants in the LEP locus are major determinants of basal leptin expression in peripheral blood mononuclear cells, and the same LEP variants that associate with leptin expression also associate with a 1.7–2-fold higher level of LPS-induced IL-6 expression; basal leptin expression significantly correlates with LPS-induced IL-6 expression, placing LEP/leptin as a trans-acting regulator of IL-6 induction in immune cells.\",\n      \"method\": \"Expression and protein quantitative trait locus mapping in PBMCs with high-density SNP typing; correlation of leptin expression levels with LPS-induced IL-6 expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — eQTL approach with correlation of leptin and IL-6 expression levels, single lab but used both protein and expression QTL readouts; mechanistic link is correlative rather than interventional\",\n      \"pmids\": [\"19942621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The porcine obesity gene (OBS/LEP) ortholog was physically mapped to pig chromosome 18 by PCR of somatic cell hybrids, and partial cDNA sequence showed 86% identity to human and 84% identity to mouse LEP cDNA, confirming conservation of the gene across mammals.\",\n      \"method\": \"RT-PCR from pig white adipose tissue, sequencing, and somatic cell hybrid PCR mapping\",\n      \"journal\": \"Animal genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and physical mapping with sequence identity confirmation, single lab\",\n      \"pmids\": [\"8856925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FABP4 knockdown in bovine adipocytes significantly decreased LEP and ADIPOQ mRNA expression (without affecting preadipocyte differentiation genes), indicating that FABP4 positively regulates LEP expression in adipocytes as part of lipid metabolism regulation.\",\n      \"method\": \"Adenovirus-mediated shRNA knockdown of FABP4 in bovine adipocytes; RT-PCR quantification of LEP, ADIPOQ, and LEPR mRNA at 24 h and 72 h\",\n      \"journal\": \"Genetics and molecular research : GMR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (mRNA measurement after knockdown), indirect regulatory relationship, bovine primary cells\",\n      \"pmids\": [\"23315880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LEP encodes leptin, a hormone secreted by white adipose tissue that regulates energy homeostasis through multiple mechanisms: it exerts tissue-specific negative autoregulation of its own expression in fat (and induces expression in skeletal muscle), requires insulin as a necessary mediator for nutritional upregulation, acts upstream of dopamine signaling for hyperphagia, and operates through SREBP-1 to drive hepatic lipogenesis while being dispensable for adiposity per se; downstream of leptin deficiency, hyperinsulinemia is a required mediator of excess adiposity, and leptin/LEP variants also modulate IL-6 production in immune cells and osteogenic differentiation via miR-874-3p targeting of the LEP 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LEP encodes leptin, a hormone secreted by white adipose tissue that operates as a central regulator of energy homeostasis, acting both on its own expression and on multiple downstream effector pathways [#0, #2]. Leptin exerts tissue-specific negative autoregulation, suppressing its own expression in adipose tissue while inducing expression in skeletal muscle, establishing inter-tissue cross-talk via the circulating hormone [#0]; gene-dosage and receptor-genotype experiments place this autocrine suppression downstream of the leptin receptor and indicate that fat mass accumulates toward a set-point defined by leptin concentration [#2]. Nutritional regulation of LEP expression in adipose tissue requires insulin as a necessary mediator [#1]. Genetic epistasis in leptin-deficient (Lep(ob/ob)) mice resolves distinct downstream branches of leptin action: dopamine signaling is required for the hyperphagia of leptin deficiency [#3], SREBP-1 mediates leptin-deficiency-induced hepatic lipogenesis but is dispensable for obesity and insulin resistance [#4], hormone-sensitive lipase is needed for full adipogenesis and modulates hypothalamic orexigenic neuropeptide expression [#5], and hyperinsulinemia is a required mediator of excess adiposity [#6]. Beyond energy balance, LEP expression is directly suppressed by miR-874-3p binding to its 3'UTR, a regulatory axis that controls osteogenic differentiation of human bone marrow mesenchymal stem cells [#7], and LEP locus variants act as a trans-acting determinant of LPS-induced IL-6 expression in immune cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that LEP is an evolutionarily conserved adipose-expressed gene, providing the molecular foundation for cross-species study of its product.\",\n      \"evidence\": \"RT-PCR cloning, sequencing, and somatic cell hybrid mapping of the porcine OBS/LEP ortholog\",\n      \"pmids\": [\"8856925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence conservation does not establish functional equivalence\", \"No functional assay of the cloned product\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved that nutritional regulation of LEP expression is not direct but requires insulin as a necessary upstream mediator.\",\n      \"evidence\": \"Streptozotocin-induced insulin deficiency in rats with Lep mRNA and plasma leptin/insulin readouts under fasting and feeding\",\n      \"pmids\": [\"9591754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the insulin signaling intermediates in adipocytes\", \"Pharmacological model may have pleiotropic effects beyond insulin loss\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that fat mass is regulated toward a set-point defined by leptin concentration and that the leptin receptor mediates autocrine suppression of LEP.\",\n      \"evidence\": \"Body composition and plasma leptin measurements in Lep(ob)/+ and Lep(rdb)/+ gene-dosage/receptor-genotype mouse comparisons\",\n      \"pmids\": [\"9575960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-mediated suppression inferred from genotype correlation, not direct intervention\", \"Molecular mechanism of autocrine feedback unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated tissue-specific negative autoregulation of LEP and leptin-mediated adipose–muscle cross-talk, refining how leptin shapes its own expression landscape.\",\n      \"evidence\": \"In vivo leptin administration and nutritional manipulation in rodents with tissue-specific mRNA measurement\",\n      \"pmids\": [\"10426312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional machinery driving opposite tissue responses unknown\", \"Physiological role of muscle LEP induction undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed dopamine signaling as a required downstream node for the hyperphagia caused by leptin deficiency, linking leptin to a defined neurotransmitter pathway.\",\n      \"evidence\": \"Genetic epistasis with dopamine-deficient x Lep(ob/ob) double mutants and L-DOPA rescue of feeding behavior\",\n      \"pmids\": [\"10802666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit-level site of dopamine action not mapped\", \"Does not address dopamine's role in body-weight set-point versus acute feeding\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Dissected leptin-deficiency phenotypes by showing SREBP-1 drives hepatic lipogenesis but is dispensable for obesity and insulin resistance, separating fatty liver from whole-body metabolic disease.\",\n      \"evidence\": \"Lep(ob/ob) x Srebp-1(-/-) double-knockout with hepatic lipid quantification, lipogenic enzyme mRNA, and metabolic phenotyping\",\n      \"pmids\": [\"11923308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the signal linking leptin deficiency to hepatic SREBP-1 activation\", \"Residual hepatic lipid pathways not characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified hormone-sensitive lipase as required for full adipogenesis in leptin deficiency and proposed an HSL-derived fatty acid signal modulating hypothalamic orexigenic neuropeptides.\",\n      \"evidence\": \"Lep(ob/ob) x HSL(-/-) double-knockout with body composition, adipose histology, and hypothalamic NPY/AgRP expression\",\n      \"pmids\": [\"14752112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Free-fatty-acid signal to hypothalamus is inferred, not directly demonstrated\", \"Cell-autonomous versus systemic role of HSL not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected LEP genetic variation to immune function, identifying leptin expression as a trans-acting correlate of LPS-induced IL-6 in immune cells.\",\n      \"evidence\": \"Expression and protein QTL mapping in PBMCs with high-density SNP typing and correlation with LPS-induced IL-6\",\n      \"pmids\": [\"19942621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link is correlative rather than interventional\", \"Causal mechanism connecting leptin levels to IL-6 induction undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established hyperinsulinemia as a necessary downstream mediator of leptin-deficiency-induced obesity, repositioning excess insulin as cause rather than consequence of adiposity.\",\n      \"evidence\": \"Graded insulin gene knockout (Ins1/Ins2 allele series) in Lep(ob/ob) mice with body composition, glycemia, and islet morphology\",\n      \"pmids\": [\"27818936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the tissues where reduced insulin limits fat accrual\", \"Relationship to leptin's central versus peripheral actions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a post-transcriptional control of LEP via direct miR-874-3p targeting of its 3'UTR that governs osteogenic differentiation, extending LEP regulation beyond metabolism.\",\n      \"evidence\": \"Luciferase reporter and RNA pull-down validation plus gain-of-function/rescue in human BMSCs with osteoblast markers and mineralization assays\",\n      \"pmids\": [\"34818977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to bone formation not tested\", \"Downstream effectors linking LEP to osteogenic markers not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular signaling intermediates that integrate leptin's autoregulation, insulin dependence, and tissue-specific downstream branches (dopamine, SREBP-1, HSL, insulin) into a unified mechanism remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct receptor-to-effector signaling chain established in the corpus\", \"Human in vivo validation of the rodent epistasis findings is absent\", \"Mechanism coupling leptin status to hepatic SREBP-1 and hypothalamic neuropeptides not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LEPR\", \"INS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}