LEPR (also called OB-R or LEP-R, CD295) is the single-pass type I transmembrane receptor for the adipocyte hormone leptin and a member of the class I cytokine receptor family, most closely related to the gp130 signal-transducing subunit of the IL-6 receptor. Alternative splicing produces a long signalling isoform (LEPRb/OB-Rb), several short isoforms (including OB-Ra) and a soluble ectodomain (isoform E) that binds circulating leptin. The ectodomain binds leptin with high affinity and leptin-induced restructuring assembles higher-order leptin:receptor complexes on the cell surface; the long isoform then signals through JAK2 and STAT3, with additional MAPK/FOS, PI3K and SHP2-ERK arms and negative feedback through SOCS3 and PTP1B. LEPRb is expressed in hypothalamic neurons, notably POMC and AgRP/NPY neurons of the arcuate nucleus, where leptin signalling stimulates POMC and represses AgRP transcription and thereby suppresses food intake and supports energy expenditure; receptor expression elsewhere (choroid plexus, endothelium, immune cells, pancreatic islets, bone) underlies peripheral leptin actions on angiogenesis, T-cell responses, insulin secretion, bone mass and reproduction. Biallelic loss-of-function LEPR mutations cause hyperphagia and severe early-onset obesity with hypogonadotropic hypogonadism, altered immune function and reduced growth hormone and thyrotropin secretion, a phenotype resembling but milder than congenital leptin deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001525 angiogenesis | IMP PMID:21771332 Glioblastoma-derived leptin induces tube formation and growt... | KEEP AS NON CORE | Summary: Angiogenesis, inferred from leptin-induced endothelial tube formation blocked by ObR antagonists (IMP, HUVEC in vitro). Reason: Leptin acting on endothelial LEPR is pro-angiogenic in vitro, but this is a peripheral, context-dependent output of leptin signalling rather than the receptor's core role in energy balance. Supporting Evidence: PMID:21771332 and if its action can be inhibited with specific ObR antagonists PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:9537324 A mutation in the human leptin receptor gene causes obesity ... | MODIFY | Summary: Transmembrane signaling receptor activity (TAS, Clement 1998). Reason: Correct but generic. LEPR is the specific receptor for leptin, and leptin receptor activity is directly supported. Proposed replacements: leptin receptor activity Supporting Evidence: PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin |
| GO:0004896 cytokine receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Cytokine receptor activity, phylogenetically inferred within the class I cytokine receptor family (IBA). Reason: LEPR is a class I cytokine receptor, but its only established ligand is leptin; the specific child term leptin receptor activity is better and is experimentally supported in human cells. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: leptin receptor activity Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor PMID:27037668 The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones |
| GO:0004896 cytokine receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Cytokine receptor activity from InterPro2GO domain mapping. Reason: Family-level domain mapping; the specific supported function is leptin receptor activity. Proposed replacements: leptin receptor activity Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin |
| GO:0005515 protein binding | IPI PMID:11279102 Sorting nexin 6, a novel SNX, interacts with the transformin... | REMOVE | Summary: Protein binding with SNX6, from a sorting-nexin/receptor interaction study (IPI). Reason: "Protein binding" is uninformative, and the sorting-nexin association concerns receptor trafficking rather than a molecular function of LEPR. Removal does not imply the interaction is false. Supporting Evidence: PMID:11279102 as well as the long form of the leptin receptor, a glycoprotein 130-associated receptor |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | REMOVE | Summary: Protein binding with GRB2, from a high-throughput SH3-domain peptide-array interactome screen (IPI). Reason: Uninformative term from a high-throughput binary screen; it conveys no specific activity of LEPR. The physiologically characterised GRB2 recruitment to LEPRb is phosphotyrosine-dependent, which an SH3 peptide array does not address. Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:18042720 Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus i... | REMOVE | Summary: Protein binding with LEPROT/OB-RGRP, a negative regulator of LEPR cell-surface expression (IPI). Reason: "Protein binding" conveys no function; OB-RGRP acts on LEPR trafficking and the informative annotation belongs to LEPROT. The interaction itself is not disputed. Supporting Evidence: PMID:18042720 We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression |
| GO:0005515 protein binding | IPI PMID:19910644 Leptin enhances the potency of circulating angiogenic cells ... | REMOVE | Summary: Protein binding with SRC and integrin subunits in leptin-stimulated circulating angiogenic cells (IPI). Reason: Downstream signalling associations recorded as uninformative "protein binding"; leptin receptor activity and the leptin-mediated signalling pathway already capture the function. Supporting Evidence: PMID:19910644 which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2- and phospholipase C (PLC) gamma-mediated activation of Src kinase |
| GO:0005515 protein binding | IPI PMID:22405007 Structure of the human obesity receptor leptin-binding domai... | MODIFY | Summary: Protein binding whose partner is leptin itself (P41159), from the crystal structure of the human ObR leptin-binding domain (IPI). Reason: The partner is the hormone ligand, so this is the receptor's core ligand-binding activity and should be expressed as leptin receptor activity rather than generic protein binding. Proposed replacements: leptin receptor activity Supporting Evidence: PMID:22405007 We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry |
| GO:0005515 protein binding | IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw... | MODIFY | Summary: Protein binding with leptin (P41159) from a human IgSF cell-surface interactome screen (IPI). Reason: The partner is leptin; this ligand-receptor interaction is the receptor's core function. Proposed replacements: leptin receptor activity Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Protein binding with leptin (P41159) from a proteome-scale binary interactome (IPI). Reason: The partner is leptin; captured more informatively as leptin receptor activity. Proposed replacements: leptin receptor activity Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Extracellular region (IEA, UniProt subcellular-location mapping). Reason: Applies to the soluble receptor (isoform E / shed ectodomain), which circulates and binds leptin; the signalling receptor itself acts at the plasma membrane. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt Antagonizes Isoform A and isoform B-mediated LEP PMID:36959263 the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms |
| GO:0005886 plasma membrane | EXP PMID:19159218 Glycoproteomics analysis of human liver tissue by combinatio... | ACCEPT | Summary: Plasma membrane, from liver tissue glycoproteomics (EXP). Reason: LEPR is a single-pass type I membrane receptor presented at the cell surface. Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor PMID:9537324 results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane (IDA, immunofluorescence curation). Reason: Consistent with a type I transmembrane cytokine receptor. Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane (IEA, combined automated methods). Reason: Consistent with the experimental localisation. Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor |
| GO:0006112 energy reserve metabolic process | TAS PMID:9537324 A mutation in the human leptin receptor gene causes obesity ... | MODIFY | Summary: Energy reserve metabolic process (TAS, Clement 1998). Reason: LEPR governs adipose energy reserves indirectly, through central control of food intake and energy expenditure; energy homeostasis is the term GO uses for the leptin-melanocortin genes and is the better fit. Proposed replacements: energy homeostasis Supporting Evidence: PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism PMID:28270795 leptin and the leptin receptor (ObR) regulate the body weight by balancing food intake and energy expenditure |
| GO:0006909 phagocytosis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Phagocytosis (IEA, Ensembl Compara transfer from rodent). Reason: Leptin can enhance macrophage phagocytosis, but that is a modulatory immune effect of leptin signalling rather than a process the receptor carries out, and there is no human evidence here. Supporting Evidence: PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:9537324 A mutation in the human leptin receptor gene causes obesity ... | MODIFY | Summary: Cell surface receptor signaling pathway (TAS). Reason: Correct but generic; the specific pathway LEPR initiates is the leptin-mediated signalling pathway. Proposed replacements: leptin-mediated signaling pathway Supporting Evidence: PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family PMID:17229951 All missense mutations resulted in impaired receptor signaling |
| GO:0007275 multicellular organism development | TAS PMID:9537324 A mutation in the human leptin receptor gene causes obesity ... | TOO GENERAL | Summary: Multicellular organism development (TAS). Reason: Multicellular organism development is entailed by the angiogenesis and bone growth annotations kept in this review, so the broad term is consistent with kept rows and cannot be removed while they stand. It adds nothing to them; the delayed puberty and growth phenotypes of receptor deficiency cited for this row are endocrine consequences of absent leptin signalling. It is recorded as too general. Supporting Evidence: PMID:9537324 results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Positive regulation of cell population proliferation (IBA). Reason: Family-level inference from cytokine receptors that drive haematopoietic proliferation. Leptin is mitogenic for some peripheral cell types, but proliferation control is not a core LEPR function. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:21771332 and if its action can be inhibited with specific ObR antagonists |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: External side of plasma membrane (IBA). Reason: The leptin-binding ectodomain faces the extracellular space, as the receptor structures show. Supporting Evidence: PMID:22405007 We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry |
| GO:0010507 negative regulation of autophagy | IDA PMID:25060689 Leptin modulates autophagy in human CD4+CD25- conventional T... | KEEP AS NON CORE | Summary: Negative regulation of autophagy in human CD4+CD25- conventional T cells (IDA). Reason: Leptin acting through LepRb inhibits autophagy in conventional T cells; a genuine but peripheral immunometabolic output. Supporting Evidence: PMID:25060689 In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells PMID:25060689 It mediates its functions through the long form of the leptin receptor (LepRb) which is part of the class I cytokine receptors |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane (IEA, InterPro2GO). Reason: Correct though uninformative; plasma membrane is the specific location already annotated. Supporting Evidence: PMID:8548812 OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor |
| GO:0016323 basolateral plasma membrane | EXP PMID:19159218 Glycoproteomics analysis of human liver tissue by combinatio... | KEEP AS NON CORE | Summary: Basolateral plasma membrane, from liver tissue glycoproteomics (EXP). Reason: Plausible for polarised cells such as hepatocytes, but not the location that defines the receptor's central function. Supporting Evidence: PMID:19159218 Glycoproteomics analysis of human liver tissue |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Basolateral plasma membrane (IEA, subcellular-location mapping). Reason: Cell-type-specific refinement of the plasma-membrane annotation. Supporting Evidence: PMID:19159218 Glycoproteomics analysis of human liver tissue |
| GO:0017046 peptide hormone binding | IPI PMID:27037668 Inhibition of Leptin-ObR Interaction Does not Prevent Leptin... | ACCEPT | Summary: Peptide hormone binding, with leptin, in a human brain-endothelial BBB model (IPI). Reason: LEPR binds the peptide hormone leptin; this is the ligand-binding half of its receptor activity. Supporting Evidence: PMID:27037668 The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones PMID:22405007 We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR |
| GO:0019221 cytokine-mediated signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: Cytokine-mediated signaling pathway (IBA). Reason: Correct at family level (class I cytokine receptor using JAK/STAT), but the specific pathway for LEPR is the leptin-mediated signalling pathway. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: leptin-mediated signaling pathway Supporting Evidence: PMID:18042720 OB-R belongs to the class I cytokine receptor family, which typically uses the JAK/STAT signaling pathwa file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and |
| GO:0019953 sexual reproduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sexual reproduction (ISS from rodent orthologues). Reason: LEPR-deficient humans have hypogonadotropic hypogonadism and absent pubertal development, so leptin signalling permits reproductive function; it is a downstream, non-core role. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism PMID:9537324 results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains |
| GO:0019955 cytokine binding | IBA GO_REF:0000033 | MODIFY | Summary: Cytokine binding (IBA). Reason: Leptin is a four-helix cytokine, so the annotation is not wrong, but the specific binding event is better stated as leptin receptor activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: leptin receptor activity Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry PMID:22405007 We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR |
| GO:0030217 T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: T cell differentiation (IEA, Ensembl Compara from rodent). Reason: Leptin modulates T-cell responses through LEPR, and LEPR-deficient patients have altered immune function; an immune output peripheral to the core energy-balance role. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism PMID:25060689 It mediates its functions through the long form of the leptin receptor (LepRb) which is part of the class I cytokine receptors |
| GO:0030217 T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: T cell differentiation (ISS). Reason: As for the IEA annotation; supported by human immune abnormalities and direct effects of leptin on T cells, but non-core. Supporting Evidence: PMID:25060689 In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
| GO:0033210 leptin-mediated signaling pathway | IDA PMID:27037668 Inhibition of Leptin-ObR Interaction Does not Prevent Leptin... | ACCEPT | Summary: Leptin-mediated signaling pathway (IDA in human brain endothelial cells). Reason: LEPR is the receptor that initiates leptin-mediated signalling; this is a core process. Supporting Evidence: PMID:27037668 The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and |
| GO:0033210 leptin-mediated signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Leptin-mediated signaling pathway (IEA). Reason: Core process of the receptor. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and PMID:36959263 The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight |
| GO:0033210 leptin-mediated signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Leptin-mediated signaling pathway (ISS). Reason: Core process; human LEPR missense mutations impair leptin signalling. Supporting Evidence: PMID:17229951 All missense mutations resulted in impaired receptor signaling |
| GO:0038021 leptin receptor activity | IDA PMID:20977476 Role of astrocytic leptin receptor subtypes on leptin permea... | ACCEPT | Summary: Leptin receptor activity (IDA, ObR subtype overexpression study). Reason: The defining molecular function of LEPR. Supporting Evidence: PMID:20977476 ObRb over-expression in C6 cells increased leptin permeation whereas ObRa over-expression showed no effect PMID:36959263 The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight |
| GO:0038021 leptin receptor activity | IDA PMID:27037668 Inhibition of Leptin-ObR Interaction Does not Prevent Leptin... | ACCEPT | Summary: Leptin receptor activity (IDA, human brain endothelial cells). Reason: The defining molecular function of LEPR. Supporting Evidence: PMID:27037668 The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones |
| GO:0038021 leptin receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Leptin receptor activity (IEA, orthologue transfer). Reason: Consistent with the direct human evidence for the same function. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family |
| GO:0038021 leptin receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Leptin receptor activity (ISS). Reason: Core function; patient missense alleles abolish receptor signalling. Supporting Evidence: PMID:17229951 All missense mutations resulted in impaired receptor signaling PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: Signaling receptor activity (IEA, ARBA). Reason: Too general for a receptor whose ligand is known; leptin receptor activity is the specific term. Proposed replacements: leptin receptor activity Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt Receptor for hormone LEP/leptin PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family |
| GO:0042593 glucose homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glucose homeostasis (IEA from rodent orthologues). Reason: Leptin signalling influences beta-cell function and glucose handling, and LEPR deficiency perturbs glucose homeostasis; a downstream physiological consequence rather than a core activity. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt regulates pancreatic beta-cell PMID:9537324 Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family |
| GO:0042593 glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Glucose homeostasis (ISS). Reason: As above. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt regulates pancreatic beta-cell |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: Signaling receptor complex (IBA). Reason: Leptin assembles 3:3 leptin:LEP-R signalling complexes on cells, so the receptor is part of a signalling receptor complex. Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | ACCEPT | Summary: Signaling receptor complex (IDA) cited to a study of PX-FERM sorting-nexin cargo recognition. Reason: The cached full text of the cited paper does not mention the leptin receptor, so the specific supporting experiment cannot be re-checked here; the curator read the full text and the location is independently correct, since leptin assembles higher-order leptin:LEP-R signalling complexes on cells. Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry |
| GO:0043235 signaling receptor complex | IPI PMID:36959263 Mechanism of receptor assembly via the pleiotropic adipokine... | ACCEPT | Summary: Signaling receptor complex (IPI) from crystallographic and cryo-EM analysis of leptin-LEP-R assemblies. Reason: Direct structural evidence that LEPR forms ligand-induced signalling complexes, together with single-molecule evidence of trimerisation on living cells. Supporting Evidence: PMID:36959263 Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry PMID:36959263 the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms |
| GO:0044321 response to leptin | IEA GO_REF:0000107 | ACCEPT | Summary: Response to leptin (IEA). Reason: Correct, if largely implied by the receptor-activity and pathway annotations. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and PMID:27037668 The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones |
| GO:0044321 response to leptin | ISS GO_REF:0000024 | ACCEPT | Summary: Response to leptin (ISS). Reason: As above. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and |
| GO:0046850 regulation of bone remodeling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of bone remodeling (IEA from rodent orthologues). Reason: Central leptin signalling regulates bone mass, but this is a peripheral output of hypothalamic LEPR signalling. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt also regulates bone mass and PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism |
| GO:0046850 regulation of bone remodeling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of bone remodeling (ISS). Reason: As above. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt also regulates bone mass and |
| GO:0046850 regulation of bone remodeling | NAS PMID:28270795 The Leptin Receptor Complex: Heavier Than Expected? | KEEP AS NON CORE | Summary: Regulation of bone remodeling (NAS, review statement). Reason: Review-level assertion of a peripheral leptin action; retained as non-core. Supporting Evidence: PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism |
| GO:0048731 system development | IEA GO_REF:0000117 | TOO GENERAL | Summary: System development (IEA, ARBA). Reason: System development is entailed by the angiogenesis and bone growth annotations kept in this review, so the broad machine-generated term is consistent with kept rows and cannot be removed while they stand. It carries no LEPR-specific evidence of its own and adds nothing to them, so it is recorded as too general. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
| GO:0051049 regulation of transport | IDA PMID:20977476 Role of astrocytic leptin receptor subtypes on leptin permea... | KEEP AS NON CORE | Summary: Regulation of transport - astrocytic ObRb overexpression increases leptin permeation across a human BBB monolayer (IDA). Reason: Supported in vitro, and relevant to how leptin reaches the hypothalamus, but transport regulation is not the receptor's core activity and antibody blockade of the leptin-ObR interface did not prevent translocation. Supporting Evidence: PMID:20977476 ObRb over-expression in C6 cells increased leptin permeation whereas ObRa over-expression showed no effect PMID:27037668 it was not inhibited by pre-treatment with 9F8 |
| GO:0060259 regulation of feeding behavior | IEA GO_REF:0000107 | ACCEPT | Summary: Regulation of feeding behavior (IEA from rodent orthologues). Reason: Hypothalamic LEPR signalling suppresses food intake; receptor loss causes hyperphagia in humans, and POMC-neuron-specific receptor deletion in mice alters feeding and body weight. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism PMID:15207242 Mice lacking leptin signaling in POMC neurons are mildly obese, hyperleptinemic, and have altered expression of hypothalamic neuropeptides |
| GO:0060259 regulation of feeding behavior | ISS GO_REF:0000024 | ACCEPT | Summary: Regulation of feeding behavior (ISS). Reason: As above. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism file:human/LEPR/LEPR-uniprot.txt In the hypothalamus, LEP acts as an appetite- |
| GO:0097009 energy homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Energy homeostasis (IEA). Reason: Core physiological process of the receptor - leptin and LEPR balance food intake against energy expenditure. Supporting Evidence: PMID:28270795 leptin and the leptin receptor (ObR) regulate the body weight by balancing food intake and energy expenditure PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
| GO:0097009 energy homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Energy homeostasis (ISS). Reason: Core process. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism file:human/LEPR/LEPR-uniprot.txt In the hypothalamus, LEP acts as an appetite- |
| GO:0097009 energy homeostasis | NAS PMID:28270795 The Leptin Receptor Complex: Heavier Than Expected? | ACCEPT | Summary: Energy homeostasis (NAS, review). Reason: Core process. Supporting Evidence: PMID:28270795 leptin and the leptin receptor (ObR) regulate the body weight by balancing food intake and energy expenditure |
| GO:0097696 cell surface receptor signaling pathway via STAT | IDA PMID:27037668 Inhibition of Leptin-ObR Interaction Does not Prevent Leptin... | ACCEPT | Summary: Cell surface receptor signaling pathway via STAT (IDA). Reason: LEPRb signals through JAK2/STAT3, and the STAT3 arm carries the energy-balance and melanocortin outputs of the receptor. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt the activation of different signaling pathways such as JAK2/STAT3 and file:human/LEPR/LEPR-uniprot.txt Control of energy homeostasis and melanocortin PMID:18042720 OB-R belongs to the class I cytokine receptor family, which typically uses the JAK/STAT signaling pathwa |
| GO:0098868 bone growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Bone growth (IEA from rodent orthologues). Reason: Indirect, neuroendocrine effect of leptin signalling. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt also regulates bone mass and PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism |
| GO:0098868 bone growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Bone growth (ISS). Reason: As above. Supporting Evidence: file:human/LEPR/LEPR-uniprot.txt also regulates bone mass and |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis (IEA). Reason: Leptin-receptor-deficient db/db mice fail to upregulate uncoupling proteins on cold exposure, so leptin signalling supports thermogenesis as part of energy-expenditure control; non-core relative to the receptor activity itself. Supporting Evidence: PMID:11003997 The accelerating effects of cold exposure on the UCP family were impaired in db/db obese mice |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:11003997 Impaired response of UCP family to cold exposure in diabetic... | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis (ISS from db/db mice). Reason: As above. Supporting Evidence: PMID:11003997 The accelerating effects of cold exposure on the UCP family were impaired in db/db obese mice |
| GO:0150104 transport across blood-brain barrier | NAS PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier. | MARK AS OVER ANNOTATED | Summary: Transport across blood-brain barrier (NAS, BBB review). LEPR regulates leptin entry but is not itself the transporter at the human BBB. Reason: The short isoform ObRa has long been proposed to shuttle leptin across the BBB, and that specific claim is what the direct experiments refute. In a human endothelial BBB model, leptin translocation was non-paracellular and endocytosis-dependent but was not blocked by an ObR-neutralising antibody that did prevent leptin-ObR binding and leptin-induced STAT3 phosphorylation in the same cells, and the authors conclude ObR is not the primary leptin transporter there, pointing to LRP-2 instead [PMID:27037668]. The second study is not a null result, and what it shows is that ObRa over-expression had no effect while ObRb over-expression in co-cultured C6 astrocytoma cells did increase leptin permeation across the endothelial monolayer [PMID:20977476]. That is astrocytic LEPR signalling regulating transport performed by the endothelium, not LEPR carrying leptin across the barrier, which is what this term asserts. Marked over-annotated rather than removed because LEPR genuinely modulates leptin entry; a regulatory term would fit, and GO has none specific to this transport. Supporting Evidence: PMID:27037668 our results demonstrate that leptin binding to and signalling through ObR is not required for efficient transport across human endothelial monolayers, indicating that ObR is not the primary leptin transporter at the human BBB PMID:20977476 Unexpectedly, ObRb over-expression in C6 cells increased leptin permeation whereas ObRa over-expression showed no effect when compared with the control group of pcDNA-transfected C6 cells PMID:20977476 the results indicate that astrocytes actively regulate leptin transport across the blood-brain barrier, a mechanism independent of reduction of paracellular permeability |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | MARK AS OVER ANNOTATED | Summary: Transport across blood-brain barrier (NAS, second BBB review). LEPR regulates leptin entry but is not itself the transporter at the human BBB. Reason: As above - a review-level assertion that the direct human BBB-model experiment does not support. Blocking leptin-ObR binding did not prevent translocation, and the authors conclude ObR is not the primary leptin transporter at the human BBB. Supporting Evidence: PMID:27037668 indicating that ObR is not the primary leptin transporter at the human BBB |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | TOO GENERAL | Summary: Animal gross anatomical part developmental process (IEA, ARBA). Reason: The broad developmental term is entailed by the angiogenesis and bone growth annotations kept in this review, so the machine-generated term is consistent with kept rows and cannot be removed while they stand. It carries no LEPR-specific evidence of its own and adds nothing to them, so it is recorded as too general. Supporting Evidence: PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
| GO:1900015 regulation of cytokine production involved in inflammatory response | NAS PMID:28270795 The Leptin Receptor Complex: Heavier Than Expected? | KEEP AS NON CORE | Summary: Regulation of cytokine production involved in inflammatory response (NAS, review). Reason: Leptin signalling shapes inflammatory cytokine output, consistent with the immune abnormalities of human receptor deficiency, but this is peripheral to the core role in energy balance. Supporting Evidence: PMID:28270795 this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism PMID:17229951 Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism |
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Download this section (compressed HTML)Q: Does the short isoform OB-Ra make any quantitatively important contribution to leptin entry into the CNS in humans, given that antibody blockade of the leptin-receptor interface did not prevent leptin translocation across a human blood-brain barrier model and ObRa overexpression did not increase permeation?
Q: Which LEPR-dependent peripheral actions of leptin (angiogenic, immune, bone) occur at physiological leptin concentrations in humans rather than being artefacts of supraphysiological dosing in vitro?
Q: How do the higher-order leptin:receptor assemblies seen structurally relate to the low abundance of the signalling-competent long isoform relative to the inactive short isoforms on hypothalamic neurons?
Experiment: Quantify isoform-resolved LEPR surface stoichiometry on human hypothalamic neurons (for example iPSC-derived POMC neurons) by single-molecule imaging, and test how obesity-associated LEPR variants alter the ligand-induced assemblies and downstream STAT3 phosphorylation.
Experiment: Compare POMC and AGRP transcriptional responses to leptin in isogenic human hypothalamic neurons carrying patient LEPR missense alleles with those in receptor-null neurons, to separate signalling-dead from partially active alleles.
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