Affinage

LEAP2

Liver-expressed antimicrobial peptide 2 · UniProt Q969E1

Length
77 aa
Mass
8.8 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LEAP2 is a hepatocyte- and enterocyte-derived peptide hormone that functions as the endogenous competitive antagonist and inverse agonist of the ghrelin receptor GHSR, opposing ghrelin to suppress food intake, growth hormone release, and glucose elevation (PMID:29233536, PMID:30543423). Originally isolated from human blood as a furin-processed 40-residue antimicrobial peptide bearing two disulfide bonds (PMID:12493837), its receptor-directed activity resides in the N-terminal region, which alone is sufficient to bind GHSR and to act as both an inverse agonist of constitutive receptor activity and an antagonist of ghrelin-evoked inositol-phosphate and calcium signaling (PMID:30543423, PMID:30666806). Mutagenesis maps this interaction to LEAP2 residues Phe4 and Arg6 contacting GHSR residues Asp99, Phe279, and Phe312, and biophysical reconstitution shows the N-terminal region stabilizes an inactive, Gq-dissociated receptor conformation that also blocks GHSR modulation of D2R-dependent Gi signaling and CaV2.2 currents (PMID:32803260, PMID:34447311). Physiologically, plasma LEAP2 falls with fasting and rises postprandially; genetic deletion sensitizes mice to ghrelin-driven feeding and GH secretion, and GHSR is required for LEAP2's anorexigenic and glucoregulatory actions, which engage hypothalamic POMC and CRF neurons and the mesolimbic dopamine system (PMID:34428557, PMID:35504998, PMID:35492241, PMID:36387867, PMID:38641041). Hepatic and intestinal LEAP2 expression is nutrient- and hormone-regulated, suppressed by beta-hydroxybutyrate and glucagon and controlled by insulin- and glucagon-responsive transcription in hepatocytes (PMID:35352108, PMID:40056903, PMID:37104087). The LEAP2–GHSR antagonism is evolutionarily ancient, conserved at least since coelacanth fish (PMID:33966114).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    Established LEAP2's molecular identity and biochemistry before any receptor role was known, defining the precursor, furin processing, disulfide architecture, and an antimicrobial activity.

    Evidence Purification from human blood ultrafiltrate, cloning, disulfide mapping, and in vitro antimicrobial assays

    PMID:12493837

    Open questions at the time
    • No receptor or signaling function identified at this stage
    • Physiological role beyond antimicrobial activity unknown
  2. 2017 High

    Answered what LEAP2 does physiologically by identifying it as an endogenous GHSR antagonist that opposes ghrelin's effects on feeding, GH, and glucose.

    Evidence In vitro GHSR activation assays plus in vivo LEAP2 administration and anti-LEAP2 neutralizing antibodies in mice

    PMID:29233536

    Open questions at the time
    • Binding site and structural basis of antagonism not defined
    • Whether activity resides in a peptide subregion unknown
  3. 2018 High

    Localized the receptor-active determinant to the LEAP2 N-terminus and distinguished inverse agonism from competitive antagonism.

    Evidence Binding, IP1, and calcium assays with full-length vs. N-terminal fragment plus in vivo food intake

    PMID:30543423

    Open questions at the time
    • Specific contact residues not yet mapped
    • Kinetic basis of antagonism not addressed
  4. 2019 Medium

    Resolved the kinetic/competitive mechanism by showing LEAP2 and ghrelin share a binding site, with slow LEAP2 dissociation converting it to functional non-competitive blockade.

    Evidence Radioligand binding and sequential vs. simultaneous ligand addition activation assays

    PMID:30666806

    Open questions at the time
    • Single lab, two methods
    • Residue-level contacts not defined
  5. 2020 Medium

    Mapped the LEAP2–GHSR interface, identifying Phe4/Arg6 on LEAP2 and Asp99/Phe279/Phe312/Phe119 on GHSR1a as the key contacts.

    Evidence Alanine scanning of LEAP2, site-directed mutagenesis of GHSR1a, binding assays, structural modeling

    PMID:32803260

    Open questions at the time
    • Structural assignments partly modeled rather than solved
    • No experimental complex structure
  6. 2021 High

    Provided the conformational mechanism of antagonism, showing the LEAP2 N-terminus stabilizes an inactive Gq-dissociated GHSR state and blocks GHSR effects on D2R-Gi and CaV2.2 currents.

    Evidence FRET with purified receptors in lipid nanodiscs and patch-clamp electrophysiology

    PMID:34447311

    Open questions at the time
    • No high-resolution structure of the LEAP2-bound receptor
    • Relevance of D2R cross-talk in vivo not established
  7. 2021 High

    Established LEAP2 as a physiologically required GHSR modulator via clean loss-of-function, linking deletion to ghrelin hypersensitivity and diet-induced metabolic phenotypes.

    Evidence LEAP2-KO mice with feeding, GH, c-Fos, metabolic, and histological readouts

    PMID:34428557

    Open questions at the time
    • Sex-specific high-fat-diet effects not fully mechanistically explained
    • Tissue source contribution not dissected
  8. 2022 High

    Placed defined neuronal populations downstream of LEAP2: a fall in LEAP2 is required for fasting activation of PVH-CRF neurons, and POMC neurons mediate its anorexigenic effect.

    Evidence GHSR-KO/ghrelin-KO models, LEAP2(1-12) infusion, AAV overexpression in arcuate nucleus, and chemogenetic POMC inhibition

    PMID:35504998 PMID:36387867

    Open questions at the time
    • Circuit connectivity between arcuate and PVH not resolved
    • POMC step shown in single lab
  9. 2022 High

    Demonstrated translational relevance and GHSR-dependence in humans, with LEAP2 infusion lowering postprandial glucose, GH, and food intake, absent in GHSR-null mice.

    Evidence Randomized placebo-controlled crossover trial in men plus GHSR-null mouse dosing

    PMID:35492241

    Open questions at the time
    • Long-term metabolic effects not assessed
    • Female human data not reported
  10. 2022 Medium

    Defined nutritional and hormonal control of LEAP2 production, identifying beta-hydroxybutyrate as a cell-autonomous suppressor of hepatic expression during fasting/ketosis.

    Evidence BHB treatment of isolated hepatocytes and oral BHB in mice with plasma LEAP2 quantification

    PMID:35352108

    Open questions at the time
    • Transcriptional mediators of BHB action not identified
    • Single lab
  11. 2023 Medium

    Extended regulation to meal composition and intestinal origin, showing nutrient-specific (oleic acid) induction of Leap2 in organoids and tissue-specific responses.

    Evidence Mouse meal challenges, intestinal organoid fatty-acid exposure, portal/systemic LEAP2 sampling

    PMID:37104087

    Open questions at the time
    • Receptors/sensors for fatty acid induction not identified
    • Single lab
  12. 2024 Medium

    Connected LEAP2 to reward and addiction circuitry, showing central LEAP2 attenuates mesolimbic dopamine responses to palatable food and alcohol.

    Evidence i.c.v. and intra-LDTg LEAP2 administration, nucleus accumbens microdialysis, and behavioral reward/consumption assays in mice and rats

    PMID:38641041 PMID:39358354

    Open questions at the time
    • Receptor identity in reward regions not directly proven
    • Single lab
  13. 2024 Medium

    Revealed sex- and hormone-dependent islet actions, with LEAP2 enhancing insulin secretion and reversing ghrelin-induced somatostatin release only in males, abolished by estradiol.

    Evidence Isolated mouse islet secretion assays with E2 and SSTR3 antagonist manipulation

    PMID:39292603

    Open questions at the time
    • Mechanism of estradiol interference unknown
    • Human islet generalizability not established
  14. 2025 Medium

    Identified the transcriptional/endocrine wiring of hepatic LEAP2, implicating insulin- and glucagon-responsive transcription factors at an enhancer-like locus, with glucagon lowering and insulin raising plasma LEAP2.

    Evidence Human somatostatin-glucagon clamp, insulin receptor antagonism in mice, and hepatocyte transcription factor binding analysis

    PMID:40056903

    Open questions at the time
    • Specific transcription factors not functionally validated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether LEAP2's ancestral antimicrobial activity and a non-GHSR receptor axis operate alongside GHSR antagonism in mammals remains unresolved.
  • No mammalian receptor for LEAP2's antimicrobial/immune actions identified
  • Relationship between antimicrobial and GHSR-antagonist functions not integrated
  • MOSPD2 axis demonstrated only in teleost

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
GHSRMOSPD2VPS35

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 LEAP2 (liver-expressed antimicrobial peptide 2) is an endogenous antagonist of the ghrelin receptor (GHSR). LEAP2 is produced in the liver and small intestine, its secretion is suppressed by fasting, and it fully inhibits GHSR activation by ghrelin in vitro. In vivo, LEAP2 blocks ghrelin-induced food intake, GH release, and maintenance of viable glucose levels during chronic caloric restriction. Neutralizing antibodies that block endogenous LEAP2 enhance ghrelin action in vivo. In vitro receptor activation assays, in vivo pharmacology (LEAP2 administration and anti-LEAP2 neutralizing antibodies in mice), secretion/expression profiling Cell metabolism High 29233536
2003 LEAP2 is synthesized as a 77-residue precursor predominantly expressed in the liver, processed by a furin-like endoprotease to generate the largest native 40-amino-acid form; the mature peptide contains two disulfide bonds (cysteines in 1-3 and 2-4 positions) and exhibits dose-dependent antimicrobial activity against selected microbial model organisms, whereas smaller variants do not. Purification from human blood ultrafiltrate, molecular cloning, structural characterization (disulfide bond mapping), in vitro antimicrobial activity assay Protein science High 12493837
2018 The N-terminal region of LEAP2 alone is sufficient for binding to GHSR and confers receptor activity. Both full-length LEAP2 and its N-terminal fragment act as inverse agonists of GHSR (reducing constitutive activity) and as competitive antagonists of ghrelin-induced inositol phosphate production and calcium mobilization. The N-terminal LEAP2 fragment inhibits ghrelin-induced food intake in mice. Receptor binding assays, IP1 accumulation assay, calcium mobilization assay, in vivo food intake assay in mice (N-terminal LEAP2 fragment vs. full-length) Journal of medicinal chemistry High 30543423
2019 LEAP2 and ghrelin compete for the same binding site on GHSR1a. When added simultaneously with ghrelin, LEAP2 behaves as a competitive antagonist; when added before ghrelin, it behaves as a non-competitive antagonist, attributable to slow dissociation from the receptor. The N-terminal fragment of LEAP2 is critical for receptor binding. Radioligand binding assays, GHSR activation assays with sequential vs. simultaneous ligand addition protocols The FEBS journal Medium 30666806
2020 Alanine-scanning mutagenesis of the LEAP2 N-terminal fragment identified Arg6 and Phe4 as essential residues for GHSR1a binding. Site-directed mutagenesis of GHSR1a revealed that Asp99 (extracellular) likely interacts with LEAP2 Arg6, while Phe279 and Phe312 (in the ligand-binding pocket) likely interact with LEAP2 Phe4, and Phe119 interacts with LEAP2 Trp5. Alanine-scanning mutagenesis of LEAP2, extensive site-directed mutagenesis of GHSR1a, receptor binding assays, structural modeling The Biochemical journal Medium 32803260
2021 LEAP2 acts as both an antagonist of ghrelin-evoked GHSR activity and an inverse agonist of constitutive GHSR activity on CaV2.2 currents in neurons. LEAP2 also prevents GHSR from modulating D2R-dependent Gi signaling on CaV2.2. Using purified receptors in lipid nanodiscs and FRET, the N-terminal region of LEAP2 was shown to stabilize an inactive conformation of GHSR dissociated from Gq protein, thereby reversing the effect of GHSR on D2R-dependent Gi activation. Patch-clamp recordings (CaV2.2 currents), FRET with purified labeled receptors assembled into lipid nanodiscs, heterologous expression system Frontiers in pharmacology High 34447311
2021 Genetic deletion of LEAP2 in mice sensitizes them to acute ghrelin-induced food intake and GH secretion. Female LEAP2-KO mice on chronic high-fat diet exhibit increased body weight, food intake, energy expenditure reduction, hepatic fat accumulation, and greater c-Fos activation in arcuate nucleus and olfactory bulb following ghrelin administration, establishing LEAP2 as a physiologically relevant modulator of GHSR signaling in vivo. LEAP2-KO mouse generation, s.c. ghrelin administration, food intake measurement, GH secretion assay, c-Fos immunostaining, metabolic cage measurements, histology Molecular metabolism High 34428557
2022 Food deprivation-induced activation of CRF neurons in the hypothalamic paraventricular nucleus requires a decrease in plasma LEAP2 levels. Preventing the fasting-induced fall of LEAP2 (via continuous systemic LEAP2(1-12) infusion) reverses the activation of PVH-CRF neurons in food-deprived mice. This effect is ghrelin-independent but requires GHSR signaling at the hypothalamic level. Genetic mouse models (GHSR-KO, ghrelin-KO), pharmacological manipulation (anti-ghrelin antibody, GHSR ligands, LEAP2 infusion), c-Fos/CRF immunostaining, arcuate nucleus ablation Cellular and molecular life sciences High 35504998
2022 LEAP2 infusion reduces postprandial plasma glucose and GH concentrations and decreases ad libitum food intake in healthy men. In wild-type mice, similar effects are observed, but not in GHSR-null mice, establishing GHSR as the mediator of LEAP2's glucoregulatory and appetite-suppressing effects. Randomized double-blind placebo-controlled crossover trial (humans), GHSR-null mouse experiments with LEAP2 dosing Cell reports. Medicine High 35492241
2022 Overexpression of LEAP2 in the arcuate nucleus via AAV reduces food intake and body weight in mice and increases POMC neuronal expression. Chemogenetic inhibition of POMC neurons abolishes the anorexigenic effect of centrally administered LEAP2, placing POMC neurons downstream of LEAP2 signaling in appetite suppression. AAV-mediated overexpression in arcuate nucleus, intracerebroventricular LEAP2 administration, chemogenetic POMC neuron inhibition (DREADD), food intake and body weight measurement Frontiers in endocrinology Medium 36387867
2021 A gut-derived LEAP2 fragment (LEAP2 38-47) stimulates insulin release in human pancreatic islets comparably to GLP-1, and this insulinotropic action is linked to attenuation of tonic GHSR activity. Small intestinal LEAP2 expression is upregulated after Roux-en-Y gastric bypass surgery. Genome-wide expression analysis of human EECs, in vitro human pancreatic islet secretion assay, GHSR activity assay, human infusion study The Journal of clinical endocrinology and metabolism Medium 33135737
2019 A fluorescent LEAP2-based probe (F-LEAP2) labels GHSR specifically on the cell surface of GHSR-expressing cells, in contrast to fluorescent ghrelin which internalizes. F-LEAP2 acts as an inverse agonist of GHSR in vitro and reduces ghrelin-induced food intake in mice following central injection, consistent with LEAP2's inverse agonist mechanism. Fluorescent ligand design, receptor binding assay, cell surface labeling vs. internalization imaging, in vivo food intake assay Molecular and cellular endocrinology Medium 31499133
2022 Beta-hydroxybutyrate (BHB) directly downregulates LEAP2 expression in isolated murine hepatocytes and reduces circulating LEAP2 levels in mice after oral BHB administration, identifying BHB as a cell-autonomous suppressor of hepatic LEAP2 production during fasting/ketosis. BHB treatment of isolated murine hepatocytes (in vitro), oral BHB administration in mice, hepatic/intestinal Leap2 expression measurement, plasma LEAP2 quantification Endocrinology Medium 35352108
2025 Glucagon infusion during somatostatin clamps significantly decreases plasma LEAP2 levels in humans. Insulin receptor antagonism offsets postprandial LEAP2 upregulation in mice. Insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Somatostatin clamp with glucagon infusion in humans, insulin receptor antagonist treatment in mice, hepatocyte-specific transcription factor binding analysis, plasma LEAP2 quantification Cell reports. Medicine Medium 40056903
2021 LEAP2 has antagonized GHSR1a since at least the emergence of coelacanth fish. Coelacanth LEAP2 and ghrelin both bind coelacanth GHSR1a with IC50 values in the nanomolar range, and coelacanth LEAP2 efficiently antagonizes coelacanth ghrelin-induced GHSR1a activation, demonstrating evolutionary conservation of the LEAP2-GHSR1a antagonism system. Binding assays and activation assays using coelacanth GHSR1a expressed in cell system, competitive inhibition analysis Amino acids Medium 33966114
2020 In teleost mudskipper, MOSPD2 (motile sperm domain-containing protein 2) was identified as a receptor mediating LEAP2's effects on monocytes/macrophages. BpMOSPD2 directly interacts with BpLEAP-2 (confirmed by Co-IP). Knockdown of BpMOSPD2 inhibited BpLEAP-2-induced chemotaxis, bacterial killing activity, and modulation of cytokine expression in MO/MΦ. Yeast two-hybrid cDNA library screening, co-immunoprecipitation, RNAi knockdown in primary mudskipper MO/MΦ, functional assays (chemotaxis, bacterial killing, cytokine qRT-PCR) Zoological research Medium 33124217
2025 In teleost mudskipper, BpLEAP2 stimulation triggers retromer-dependent intracellular trafficking of BpMOSPD2 from the ER to early endosomes and then to the plasma membrane. Knockdown of retromer subunits (VPS35, VPS26, VPS29) abolishes BpMOSPD2 membrane localization and BpLEAP2-induced MO/MΦ migration. Co-IP with mass spectrometry confirmed direct interaction between BpMOSPD2 and BpVPS35. Subcellular fractionation, immunofluorescence, Co-IP combined with mass spectrometry, retromer subunit knockdown (RNAi), migration assay Zoological research Medium 41017400
2016 LEAP2 overexpression in Xenopus embryos impairs normal embryonic development. In pluripotent embryonic cells, LEAP2 stimulates FGF signaling while reducing the activin response. LEAP2 also blocks FGF-induced migration of human vascular endothelial cells (HUVEC), suggesting an extracellular modulatory role for LEAP2 on FGF and activin signals. Xenopus gain-of-function overexpression, animal cap assays, HUVEC migration assay Peptides Low 27335344
2024 Central (i.c.v.) administration of LEAP2 in mice reduces feeding and intake of palatable foods, attenuates accumbal dopamine release associated with palatable food exposure, and reduces the rewarding memory of high-preference foods. LEAP2 is expressed in reward-related brain areas including the laterodorsal tegmental area (LDTg), and infusion of LEAP2 into LDTg transiently reduces acute palatable food intake. i.c.v. and intra-LDTg LEAP2 administration in mice, microdialysis (accumbal dopamine), in situ expression profiling, behavioral food intake tests Progress in neurobiology Medium 38641041
2024 LEAP2 enhances insulin secretion in isolated islets from male but not female mice, and reverses acyl-ghrelin-stimulated somatostatin release in males but not females. Estradiol (E2) pre-treatment of male islets abolished both AG-induced insulinostatic effects and their reversal by LEAP2, demonstrating sex- and hormone-dependent modulation of islet function by LEAP2 acting via GHSR1a. Isolated mouse islet secretion experiments (radioimmunoassay), E2 pre-treatment, SSTR3 antagonist experiments, qPCR of islet gene expression The Journal of endocrinology Medium 39292603
2023 LEAP2 dietary regulation depends on meal composition: all meal challenges except fish oil increased jejunal Leap2 expression, while only a mixed meal increased liver Leap2 expression. Leap2 expression correlated with hepatic glycogen and jejunal lipid levels. Oleic acid (but not docosahexaenoic acid) increased Leap2 expression in intestinal organoids, indicating nutrient-specific cell-autonomous regulation. Mouse meal challenge experiments, intestinal organoid culture with specific fatty acids, jejunal/hepatic gene expression analysis, portal vein plasma LEAP2 measurement FASEB journal Medium 37104087
2022 Transcription factor CDX4 binds to the LEAP2 promoter region in the small intestine and positively regulates LEAP2 expression, as demonstrated by transcription factor prediction and dual luciferase assay. Dual luciferase reporter assay, transcription factor binding site analysis Animals Low 36552416
2024 Central LEAP2 administration in mice prevents alcohol-induced locomotor stimulation, suppresses the memory of alcohol reward, attenuates dopamine release in the nucleus accumbens caused by alcohol, and reduces alcohol consumption in rats. These effects parallel LEAP2's modulation of the mesolimbic dopamine system. i.c.v. LEAP2 administration in mice/rats, locomotor activity measurement, conditioned place preference, in vivo microdialysis (nucleus accumbens dopamine), voluntary alcohol consumption paradigm Translational psychiatry Medium 39358354
2023 In fish (Acrossocheilus fasciatus), the linear (disulfide-free) form of LEAP2 mature peptide shows potent antimicrobial activity and disrupts bacterial cell membrane integrity, while the oxidized (disulfide-bonded, cyclic) form has weak or no antibacterial activity. This establishes that disulfide bonds are not required for—and in fact impair—the antimicrobial function of LEAP2. Chemical synthesis of linear vs. oxidized LEAP2, circular dichroism spectroscopy, in vitro MIC assays, bacterial membrane integrity assay BMC veterinary research Medium 38835040

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor. Cell metabolism 301 29233536
2003 Isolation and biochemical characterization of LEAP-2, a novel blood peptide expressed in the liver. Protein science : a publication of the Protein Society 179 12493837
2018 N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor. Journal of medicinal chemistry 150 30543423
2005 The catfish liver-expressed antimicrobial peptide 2 (LEAP-2) gene is expressed in a wide range of tissues and developmentally regulated. Molecular immunology 96 16310050
2004 Discovery and characterization of two types of liver-expressed antimicrobial peptide 2 (LEAP-2) genes in rainbow trout. Veterinary immunology and immunopathology 78 15350756
2019 Identifying the binding mechanism of LEAP2 to receptor GHSR1a. The FEBS journal 73 30666806
2022 LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men. Cell reports. Medicine 67 35492241
2021 LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue. Molecular metabolism 65 34428557
2014 Molecular characterization of LEAP-2 cDNA in common carp (Cyprinus carpio L.) and the differential expression upon a Vibrio anguillarum stimulus; indications for a significant immune role in skin. Fish & shellfish immunology 62 24418455
2015 Molecular characterization of the liver-expressed antimicrobial peptide 2 (LEAP-2) in a teleost fish, Plecoglossus altivelis: antimicrobial activity and molecular mechanism. Molecular immunology 58 25749706
2005 Porcine liver-expressed antimicrobial peptides, hepcidin and LEAP-2: cloning and induction by bacterial infection. Developmental and comparative immunology 55 16051358
2021 LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity. Frontiers in endocrinology 52 34512549
2019 Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model. Journal of neuroendocrinology 51 31469195
2009 Expression and functional analyses of liver expressed antimicrobial peptide-2 (LEAP-2) variant forms in human tissues. Cellular immunology 51 20038463
2018 Ghrelin and LEAP-2: Rivals in Energy Metabolism. Trends in pharmacological sciences 50 30037389
2013 Molecular cloning and expression analysis of liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 genes in the blunt snout bream (Megalobrama amblycephala). Fish & shellfish immunology 43 23748217
2009 Molecular cloning and expression analysis of the liver-expressed antimicrobial peptide 2 (LEAP-2) gene in grass carp. Veterinary immunology and immunopathology 43 19716607
2020 Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance. European journal of endocrinology 41 31770106
2019 Development of a novel fluorescent ligand of growth hormone secretagogue receptor based on the N-Terminal Leap2 region. Molecular and cellular endocrinology 39 31499133
2021 Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment. The Journal of clinical endocrinology and metabolism 37 33135737
2020 Circulating LEAP-2 is associated with puberty in girls. International journal of obesity (2005) 34 33139887
2016 The protection effect of LEAP-2 on the mudskipper (Boleophthalmus pectinirostris) against Edwardsiella tarda infection is associated with its immunomodulatory activity on monocytes/macrophages. Fish & shellfish immunology 33 27765699
2014 Characterization, evolution and functional analysis of the liver-expressed antimicrobial peptide 2 (LEAP-2) gene in miiuy croaker. Fish & shellfish immunology 31 25180825
2022 GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner. Cellular and molecular life sciences : CMLS 30 35504998
2014 Molecular characterization and functional analysis of two distinct liver-expressed antimicrobial peptide 2 (LEAP-2) genes in large yellow croaker (Larimichthys crocea). Fish & shellfish immunology 30 24727197
2022 Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2. Endocrinology 29 35352108
2021 LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling. Frontiers in pharmacology 28 34447311
2019 Host defense peptide LEAP-2 contributes to monocyte/macrophage polarization in barbel steed (Hemibarbus labeo). Fish & shellfish immunology 28 30641185
2020 MOSPD2 is a receptor mediating the LEAP-2 effect on monocytes/macrophages in a teleost, Boleophthalmus pectinirostris. Zoological research 25 33124217
2010 Expression of chicken LEAP-2 in the reproductive organs and embryos and in response to Salmonella enterica infection. Veterinary research communications 24 20526889
2023 Antagonic effect of ghrelin and LEAP-2 on hepatic stellate cell activation and liver fibrosis in obesity-associated nonalcoholic fatty liver disease. European journal of endocrinology 23 37358209
2022 Serum levels of ghrelin and LEAP2 in patients with type 2 diabetes mellitus: correlation with circulating glucose and lipids. Endocrine connections 22 35521798
2024 A long-acting LEAP2 analog reduces hepatic steatosis and inflammation and causes marked weight loss in mice. Molecular metabolism 21 38697291
2022 Involvement of POMC neurons in LEAP2 regulation of food intake and body weight. Frontiers in endocrinology 21 36387867
2021 High Coexpression of the Ghrelin and LEAP2 Receptor GHSR With Pancreatic Polypeptide in Mouse and Human Islets. Endocrinology 21 34289060
2013 Immune activation in HIV/HCV-infected patients is associated with low-level expression of liver expressed antimicrobial peptide-2 (LEAP-2). Journal of clinical pathology 21 23940131
2024 Decoding the influence of central LEAP2 on food intake and its effect on accumbal dopamine release. Progress in neurobiology 20 38641041
2023 Postprandial Increases in Liver-Gut Hormone LEAP2 Correlate with Attenuated Eating Behavior in Adults Without Obesity. Journal of the Endocrine Society 20 37287649
2023 Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner. European journal of nutrition 19 38157050
2020 Identifying key residues and key interactions for the binding of LEAP2 to receptor GHSR1a. The Biochemical journal 19 32803260
2025 Critical Insights Into LEAP2 Biology and Physiological Functions: Potential Roles Beyond Ghrelin Antagonism. Endocrinology 18 39823403
2020 Molecular characterization and antibacterial immunity functional analysis of liver-expressed antimicrobial peptide 2 (LEAP-2) gene in golden pompano (Trachinotus ovatus). Fish & shellfish immunology 18 32891790
2023 High-Fat Diet Induces Resistance to Ghrelin and LEAP2 Peptide Analogs in Mice. Physiological research 17 38015760
2021 LEAP2 has antagonized the ghrelin receptor GHSR1a since its emergence in ancient fish. Amino acids 17 33966114
2021 Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome. Molecules (Basel, Switzerland) 17 35011234
2023 Host defence peptide LEAP2 contributes to antimicrobial activity in a mustache toad (Leptobrachium liui). BMC veterinary research 16 36765333
2024 The effects of ghrelin and LEAP-2 in energy homeostasis are modulated by thermoneutrality, high-fat diet and aging. Journal of endocrinological investigation 15 38337094
2024 LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents. Translational psychiatry 14 39358354
2023 The dietary regulation of LEAP2 depends on meal composition in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 37104087
2023 Identification of antibacterial activity of LEAP2 from Antarctic icefish Chionodraco hamatus. Journal of fish diseases 14 37245215
2020 Characterization and functional analysis of liver-expressed antimicrobial peptide-2 (LEAP-2) from golden pompano Trachinotus ovatus (Linnaeus 1758). Fish & shellfish immunology 14 32562868
2019 The next big LEAP2 understanding ghrelin function. The Journal of clinical investigation 14 31424426
2019 A novel LEAP-2 in diploid hybrid fish (Carassius auratus cuvieri ♀ × Carassius auratus red var. ♂) confers protection against bacteria-stimulated inflammatory response. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 14 31707088
2024 LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans. Diabetes, obesity & metabolism 13 39140219
2023 LEAP2 is associated with cardiometabolic markers but is unchanged by antidiabetic treatment in people with prediabetes. American journal of physiology. Endocrinology and metabolism 13 37436962
2022 Chicken LEAP2 Level Substantially Changes with Feed Intake and May Be Regulated by CDX4 in Small Intestine. Animals : an open access journal from MDPI 13 36552416
2021 LEAP-2/ghrelin interplay in adult growth hormone deficiency: Cause or consequence? A pilot study. IUBMB life 11 33991145
2024 The LEAP2 Response to Cancer-Related Anorexia-Cachexia Syndrome in Male Mice and Patients. Endocrinology 10 39331742
2025 Regulation of LEAP2 by insulin and glucagon in mice and humans. Cell reports. Medicine 9 40056903
2023 LEAP2 is a more conserved ligand than ghrelin for fish GHSRs. Biochimie 9 36669723
2016 Overexpression of Leap2 impairs Xenopus embryonic development and modulates FGF and activin signals. Peptides 9 27335344
2023 New insights into the antimicrobial mechanism of LEAP2 mutant zebrafish under Aeromonas hydrophila infection using transcriptome analysis. Fish & shellfish immunology 8 37977545
2016 Characterization and expression of non-polymorphic liver expressed antimicrobial peptide 2: LEAP-2 in the Japanese quail, Coturnix japonica. Animal science journal = Nihon chikusan Gakkaiho 8 27313148
2025 Peptide with Dual Roles in Immune and Metabolic Regulation: Liver-Expressed Antimicrobial Peptide-2 (LEAP-2). Molecules (Basel, Switzerland) 7 39860298
2024 Identification of antibacterial activity of liver-expressed antimicrobial peptide 2 (LEAP2) from primitive vertebrate lamprey. Fish & shellfish immunology 7 38311092
2024 Satiety Hormone LEAP2 After Low-Calorie Diet With/Without Endobarrier Insertion in Obesity and Type 2 Diabetes Mellitus. Journal of the Endocrine Society 7 39659543
2024 Simultaneous treatment with palm-LEAP2(1-14) and feeding high-fat diet attenuates liver lipid metabolism but not obesity: Sign of selective resistance to palm-LEAP2(1-14). Molecular and cellular endocrinology 7 39689753
2019 Subfunctionalization and evolution of liver-expressed antimicrobial peptide 2 (LEAP2) isoform genes in Siberian sturgeon (Acipenser baerii), a primitive chondrostean fish species. Fish & shellfish immunology 7 31319209
2025 Effects of central injection of liver-expressed antimicrobial peptide-2 (LEAP2) on feed intake in broiler chickens: interactions with opioidergic and serotonergic systems. Veterinary research communications 6 40542992
2025 Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice. Diabetes 6 40590720
2024 Preliminary study on the diagnostic value of LEAP-2 and CK18 in biopsy-proven MAFLD. BMC gastroenterology 6 38778244
2022 LEAP2: Next game-changer of pharmacotherapy for overweight and obesity? Cell reports. Medicine 6 35492250
2016 Enrofloxacin and Probiotic Lactobacilli Influence PepT1 and LEAP-2 mRNA Expression in Poultry. Probiotics and antimicrobial proteins 6 27503362
2014 LEAP-2, LL-37 and RNase7 in tonsillar tissue: downregulated expression in seasonal allergic rhinitis. Pathogens and disease 6 24821514
2025 LEAP2 as a therapeutic target in obesity and cardiometabolic disorders. Reviews in endocrine & metabolic disorders 5 41284160
2024 The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner. The Journal of endocrinology 5 39292603
2023 Loss of LEAP-2 alleviates obesity-induced myocardial injury by regulating macrophage polarization. Experimental cell research 5 37414204
2025 LEAP2 triggers retromer-mediated membrane trafficking of MOSPD2 to promote chemotaxis in teleost monocytes/macrophages. Zoological research 4 41017400
2024 CRISPR/Cas9-induced LEAP2 and GHSR1a knockout mutant zebrafish displayed abnormal growth and impaired lipid metabolism. General and comparative endocrinology 4 38830459
2024 Genetic variants of LEAP2 are associated with anthropometric traits and circulating insulin-like growth factor-1 concentration: A UK Biobank study. Diabetes, obesity & metabolism 4 38888057
2024 Ghrelin-LEAP2 interactions along the stomach-liver axis. Endocrine journal 4 39756956
2023 CRFB5a, a Subtype of Japanese Eel (Anguilla japonica) Type I IFN Receptor, Regulates Host Antiviral and Antimicrobial Functions through Activation of IRF3/IRF7 and LEAP2. Animals : an open access journal from MDPI 4 37835763
2025 Molecular characterization and functional prioritization of CD46, IL6R, KLRC1, LEAP2 and SMOX as candidate targets in acute kidney injury. International journal of biological macromolecules 3 40683494
2024 Structure-activity relationships of the intramolecular disulphide bonds in LEAP2, an antimicrobial peptide from Acrossocheilus fasciatus. BMC veterinary research 3 38835040
2025 Serum LEAP2 Levels Across the Spectrum of Metabolic Dysfunction-Associated Fatty Liver Disease: A Potential Noninvasive Biomarker for Severity Stratification. Diabetes, metabolic syndrome and obesity : targets and therapy 2 40726500
2025 Ghrelin and LEAP2: Their Interaction Effect on Appetite Regulation and the Alterations in Their Levels Following Bariatric Surgery. Medicina (Kaunas, Lithuania) 2 40870497
2024 Quail GHRL and LEAP2 gene cloning, polymorphism detection, phylogenetic analysis, tissue expression profiling and its association analysis with feed intake. Gene 2 38636815
2024 Deficiency of leap2 promotes somatic growth in zebrafish: Involvement of the growth hormone system. Heliyon 2 39347412
2025 Molecular characterization of an antimicrobial peptide LEAP-2 in Onychostoma macrolepis: Expression pattern, antimicrobial ability and immunomodulation function. International journal of biological macromolecules 1 40121727
2026 Additive effect of leptin and palm-LEAP2(1-14) ameliorates obesity-induced metabolic stress in ob/ob mice. European journal of pharmacology 0 41520761
2026 LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging. Life sciences 0 41571146
2026 LEAP2 modulates β-adrenergic triggered cardiac responses and provokes antihypertensive effects. Life sciences 0 41619965
2026 LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men With Obesity. Diabetes 0 41911360
2025 Identification and characterisation of LEAP2 from Chinese spiny frogs (Quasipaa spinosa) with antimicrobial and macrophage activation properties. BMC veterinary research 0 40082911
2025 LEAP2: from feeding regulation to its implications in eating disorders. Physiology & behavior 0 40618862
2025 Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 diabetes. iScience 0 41069857
2025 LEAP2 deficiency does not impair essential iron-dependent functions in zebrafish. Fish & shellfish immunology 0 41077091
2025 Does fetal or maternal leap-2 level affect infant birth weight? BMC pregnancy and childbirth 0 41299349
2025 Effect of intracerebroventricular (ICV) injection of antimicrobial peptide expressed in the body-2 (LEAP-2) and its interaction with cannabinoid and ghrelin systems on food intake in broiler chickens. Poultry science 0 41406822
2025 Exercise maintains LEAP2 levels after weight loss in females with obesity. iScience 0 41503208

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