LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor
Open accessAbstract
Ghrelin, an appetite-stimulatory hormone secreted by the stomach, was discovered as a ligand for the growth hormone secretagogue receptor (GHSR). Through GHSR, ghrelin stimulates growth hormone (GH) secretion, a function that evolved to protect against starvation-induced hypoglycemia. Though the biology mediated by ghrelin has been described in great detail, regulation of ghrelin action is poorly understood. Here, we report the discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist of GHSR. LEAP2 is produced in the liver and small intestine, and its secretion is suppressed by fasting. LEAP2 fully inhibits GHSR activation by ghrelin and blocks the major effects of ghrelin in vivo, including food intake, GH release, and maintenance of viable glucose levels during chronic caloric restriction. In contrast, neutralizing antibodies that block endogenous LEAP2 function enhance ghrelin action in vivo. Our findings reveal a mechanism for fine-tuning ghrelin action in response to changing environmental conditions.
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LEAP2 is an endogenous antagonist of the ghrelin receptor, or growth hormone secretagogue receptor (GHSR).
“Importantly, LEAP2 was reported to be an endogenous antagonist of the ghrelin receptor, or growth hormone secretagogue receptor (GHSR).”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [47]
LEAP2 can fully blunt GHSR activation by ghrelin, thus reducing food intake and growth hormone release.
“Indeed, LEAP2 can fully blunt GHSR activation by ghrelin, thus reducing food intake and growth hormone (GH) release 47.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [47]
Comparing RNA sequencing of jejunum and stomach between sham and gastric sleeve bypass allowed the identification of LEAP2, an endogenous antagonist of the ghrelin receptor, which may contribute to the efficiency of gastric bypass.
“Comparing RNA sequencing of jejunum and stomach when comparing sham and gastric sleeve bypass allowed the identification of LEAP2, an endogenous antagonist of the ghrelin receptor, which may contribute to the efficiency of gastric bypass 47.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [47]
Cites
Trapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 11,930 · see citing works
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., & Kangawa, K. (1999) · Nature · doi:10.1038/45230 · Cited by 8,479 · see citing works
Ghrelin induces adiposity in rodents
Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000) · Nature · doi:10.1038/35038090 · Cited by 3,949 · see citing works
A role for ghrelin in the central regulation of feeding
Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., & Matsukura, S. (2001) · Nature · doi:10.1038/35051587 · Cited by 3,443 · cited 1× · see citing works
“Activation of GHSR in hypothalamic neurons stimulates an orexigenic neural pathway, resulting in increased food intake (Nakazato et al., 2001).”
BackgroundPeptide therapeutics: current status and future directions
Fosgerau, K., & Hoffmann, T. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.10.003 · Cited by 3,060 · see citing works
A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans
Cummings, D. E., Purnell, J. Q., Frayo, R. S., Schmidova, K., Wisse, B. E., & Weigle, D. S. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1714 · Cited by 2,940 · see citing works
Ghrelin: Structure and Function
Kojima, M., & Kangawa, K. (2005) · Physiological Reviews · doi:10.1152/physrev.00012.2004 · Cited by 2,810 · see citing works
(2012) · doi:10.1016/j.jmoldx.2011.08.002 · Cited by 2,567 · see citing works
Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
Cummings, D., Weigle, D., Frayo, R. S., Breen, P. A., Ma, M. K., Dellinger, E., & Purnell, J. Q. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa012908 · Cited by 2,499 · see citing works
Fast and SNP-tolerant detection of complex variants and splicing in short reads
Wu, T. D., & Nacu, S. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq057 · Cited by 1,894 · see citing works
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein
Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., & Barsh, G. S. (1997) · Science · doi:10.1126/science.278.5335.135 · Cited by 1,881 · see citing works
Cowley, M. A., Smith, R. G., Diano, S., Tschöp, M., Pronchuk, N., Grove, K. L., Strasburger, C. J., Bidlingmaier, M., Esterman, M., Heiman, M. L., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00063-1 · Cited by 1,679 · see citing works
Cahill, G. F. (2006) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.26.061505.111258 · Cited by 1,318 · see citing works
Zolotukhin, S., Byrne, B. J., Mason, E. G., Zolotukhin, I., Potter, M., Chesnut, K. A., Summerford, C., Samulski, R. J., & Muzyczka, N. (1999) · Gene Therapy · doi:10.1038/sj.gt.3300938 · Cited by 1,317 · see citing works
Yang, J., Brown, M. S., Liang, G., Grishin, N., & Goldstein, J. (2008) · Cell · doi:10.1016/j.cell.2008.01.017 · Cited by 1,191 · see citing works
Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
Gao, G., Vandenberghe, L. H., Alvira, M. R., Lu, Y., Calcedo, R., Zhou, X., & Wilson, J. M. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6381-6388.2004 · Cited by 1,070 · see citing works
Müller, T. D., Nogueiras, R., Andermann, M. L., Andrews, Z. B., Anker, S. D., Argente, J., Batterham, R. L., Benoit, S. C., Bowers, C. Y., Broglio, F., et al. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.03.005 · Cited by 1,034 · see citing works
Ghrelin octanoylation mediated by an orphan lipid transferase
Gutierrez, J. A., Solenberg, P., Perkins, D., Willency, J. A., Knierman, M. D., Jin, Z., Witcher, D., Luo, S., Onyia, J. E., & Hale, J. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0800708105 · Cited by 827 · see citing works
Sun, Y., Wang, P., Zheng, H., & Smith, R. G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305930101 · Cited by 743 · see citing works
Elevated plasma ghrelin levels in Prader–Willi syndrome
Cummings, D. E., Clément, K., Purnell, J., Vaisse, C., Foster, K. E., Frayo, R. S., Schwartz, M., Basdevant, A., & Weigle, D. (2002) · Nature Medicine · doi:10.1038/nm0702-643 · Cited by 622 · see citing works
High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist
Holst, B., Cygankiewicz, A., Jensen, T. H., Ankersen, M., & Schwartz, T. W. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0069 · Cited by 515 · see citing works
Zhao, T., Liang, G., Li, R. L., Xie, X., Sleeman, M. W., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Goldstein, J. L., & Brown, M. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002271107 · Cited by 427 · see citing works
Genetic approaches to studying energy balance: perception and integration
Barsh, G. S., & Schwartz, M. W. (2002) · Nature Reviews Genetics · doi:10.1038/nrg862 · Cited by 417 · see citing works
Cyclic Peptides as Therapeutic Agents and Biochemical Tools
Joo, S. H. (2012) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2012.20.1.019 · Cited by 359 · see citing works
Mechanisms underlying weight loss after bariatric surgery
Miras, A. D., & le Roux, C. W. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.119 · Cited by 344 · see citing works
Wilson, H., Chambers, A. P., Ryan, K. K., Li, B., Sandoval, D. A., Stoffers, D. A., Drucker, D. J., Pérez–Tilve, D., & Seeley, R. J. (2013) · Diabetes · doi:10.2337/db12-1498 · Cited by 286 · see citing works
Christopoulos, A., Changeux, J., Catterall, W. A., Fabbro, D., Burris, T. P., Cidlowski, J. A., Olsen, R. W., Peters, J. A., Neubig, R. R., Pin, J., et al. (2014) · Pharmacological Reviews · doi:10.1124/pr.114.008862 · Cited by 238 · see citing works
Isolation and biochemical characterization of LEAP‐2, a novel blood peptide expressed in the liver
Krause, A., Sillard, R., Kleemeier, B., Klüver, E., Maronde, E., Conejo-Garcia, J. R., Forssmann, W. G., Schulz‐Knappe, P., Nehls, M. C., Wattler, F., et al. (2003) · Protein Science · doi:10.1110/ps.0213603 · Cited by 232 · see citing works
Seeley, R., Chambers, A. P., & Sandoval, D. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.01.001 · Cited by 218 · see citing works
Leggio, L., Zywiak, W. H., Fricchione, S. R., Edwards, S. M., de la Monte, S. M., Swift, R. M., & Kenna, G. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.03.019 · Cited by 162 · see citing works
McFarlane, M., Brown, M. S., Goldstein, J. L., & Zhao, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.04.007 · Cited by 150 · see citing works
Li, R. L., Sherbet, D. P., Elsbernd, B. L., Goldstein, J. L., Brown, M. S., & Zhao, T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.358051 · Cited by 127 · see citing works
Surviving Starvation: Essential Role of the Ghrelin-Growth Hormone AxisPreprint
Goldstein, J. L., Zhao, T. J., Li, R. L., Sherbet, D. P., Liang, G., & Brown, M. S. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010447 · Cited by 117 · see citing works
Evidence for Acyl-Ghrelin Modulation of Growth Hormone Release in the Fed State
Nass, R. M., Farhy, L. S., Liu, J., Prudom, C. E., Johnson, M. L., Veldhuis, P. P., Pezzoli, S. S., Oliveri, M. C., Gaylinn, B. D., Geysen, H. M., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2234 · Cited by 90 · see citing works
Zhang, Y., Fang, F., Goldstein, J. L., Brown, M. S., & Zhao, T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423643112 · Cited by 80 · see citing works
Structural and Functional Analysis of Human Liver‐Expressed Antimicrobial Peptide 2
Henriques, S. T., Tan, C. C., Craik, D. J., & Clark, R. J. (2010) · ChemBioChem · doi:10.1002/cbic.201000400 · Cited by 72 · see citing works
Howard, A., Townes, C. L., Milona, P., Nile, C. J., Michailidis, G., & Hall, J. (2009) · Cellular Immunology · doi:10.1016/j.cellimm.2009.11.010 · Cited by 66 · see citing works
The Growth Hormone Secretagogue Receptor
Cruz, C. C., & Smith, R. G. (2007) · Vitamins and hormones · doi:10.1016/s0083-6729(06)77004-2 · Cited by 59 · see citing works
Peptide ligand recognition by G protein-coupled receptors
Krumm, B., & Grisshammer, R. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00048 · Cited by 37 · see citing works
Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling
Galon-Tilleman, H., Yang, H., Bednarek, M. A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.748103 · Cited by 37 · see citing works
Self-citationLow-dose ghrelin infusion — Evidence against a hormonal role in food intake
Lippl, F., Erdmann, J., Steiger, A., Lichter, N., Czogalla‐Peter, C., Bidlingmaier, M., Tholl, S., & SCHUSDZIARRA, V. (2011) · Regulatory Peptides · doi:10.1016/j.regpep.2011.11.005 · Cited by 35 · see citing works
Thomas, M. A., Ryu, V., & Bartness, T. J. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00216.2015 · Cited by 27 · see citing works
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Hagemann, C. A., Jensen, M. S., Holm, S., Gasbjerg, L. S., Byberg, S., Skov-Jeppesen, K., Hartmann, B., Holst, J. J., Dela, F., Vilsbøll, T., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100582 · Cited by 81 · see citing works
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- Authors
- Ge, X., Yang, H., Bednarek, M. A., Galon-Tilleman, H., Chen, P., Chen, M., Lichtman, J. S., Wang, Y., Dalmas, O., Yin, Y., Tian, H., Jermutus, L., Grimsby, J., Rondinone, C. M., Konkar, A., & Kaplan, D. D.
- Affiliations
- NGM Biopharmaceuticals (United States) (US)
- Corresponding author
- Ge, Xuecai
- Kaplan, Daniel D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 27
- Issue
- 2
- Pages
- 461-469.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2774279346
- Cited by
- 376
- References
- 42
- Citations by year
- 2026: 47 · 2025: 53 · 2024: 54 · 2023: 47 · 2022: 49 · 2021: 49 · 2020: 30 · 2019: 34 · 2018: 12
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- LEAP2, ghrelin, growth hormone secretagogue receptor, appetite regulation, dietary intake, growth hormone secretion, fasting, caloric restriction, hypoglycemia, liver, small intestine, antimicrobial peptides, neutralizing antibodies
- MeSH terms
- Animals, Eating, Fasting, Female, Humans, Intestine, Small, Liver, Male, Protein Binding, Growth Hormone, Caloric Restriction, Bariatric Surgery, Mice, Rats, Ghrelin, Receptors, Ghrelin, Hepcidins
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