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Peer-reviewedCC BYCurrent Obesity Reports

The Ghrelin-LEAP2 System in Obesity and Diabetes: Pathophysiological Roles and Therapeutic Potential

  • Isabela Valdés Calero1
  • Gema Frühbeck2,3,4,5,6
  • Amaia Rodrı́guez7,8,9,10
10 affiliations
  1. 1Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Avda. Pío XII 36, 31008, Pamplona, Spain
  2. 2CIBER de Fisiopatología de La Obesidad y La Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. [email protected]
  3. 3Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Avda. Pío XII 36, 31008, Pamplona, Spain. [email protected]
  4. 4Institute for Nutrition and Health, University of Navarra, Pamplona, Spain. [email protected]
  5. 5Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain. [email protected]
  6. 6Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. [email protected]
  7. 7CIBER de Fisiopatología de La Obesidad y La Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. [email protected]
  8. 8Institute for Nutrition and Health, University of Navarra, Pamplona, Spain. [email protected]
  9. 9Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain. [email protected]
  10. 10Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. [email protected]
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Abstract

PURPOSEOF REVIEW: Ghrelin is a gut-derived acylated hormone that regulates appetite, food reward-related behaviours, glycaemic control, and lipid metabolism. These actions are primarily mediated through activation of the growth hormone secretagogue receptor (GHSR), which is highly expressed in the brain and also present in key metabolic organs. Ghrelin acylation by ghrelin O-acyltransferase (GOAT) is required for receptor binding and biological activity. This review examines the physiological and pathophysiological roles of ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), with particular emphasis on its relevance to obesity and type 2 diabetes. RECENT FINDINGS: LEAP2 has recently been identified as an endogenous antagonist and inverse agonist of GHSR that counteracts ghrelin signalling. Emerging evidence indicates that obesity and type 2 diabetes are generally associated with reduced circulating ghrelin levels and increased LEAP2 concentrations, particularly in the presence of insulin resistance. These reciprocal changes support the concept that the ghrelin/LEAP2 ratio functions as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, and may influence metabolic responses to nutritional status and weight loss. The ghrelin-LEAP2 system represents a key regulatory pathway in metabolic homeostasis and a promising therapeutic target for obesity and related metabolic disorders. Pharmacological strategies targeting this axis, including ghrelin antagonists, LEAP2 analogues, GOAT inhibitors, and GHSR inverse agonists, are under active investigation, although further studies are required to establish their long-term efficacy and safety.

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Cite

BibTeXRIS
BibTeX
@article{calero2026ghrelinleap2,
  title = {{The Ghrelin-LEAP2 System in Obesity and Diabetes: Pathophysiological Roles and Therapeutic Potential}},
  author = {Isabela Valdés Calero and Gema Frühbeck and Amaia Rodrı́guez},
  journal = {Current Obesity Reports},
  year = {2026},
  month = jun,
  doi = {10.1007/s13679-026-00728-1},
  url = {https://doi.org/10.1007/s13679-026-00728-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The Ghrelin-LEAP2 System in Obesity and Diabetes: Pathophysiological Roles and Therapeutic Potential
AU  - Isabela Valdés Calero
AU  - Gema Frühbeck
AU  - Amaia Rodrı́guez
PY  - 2026
DA  - 2026/06/12
JO  - Current Obesity Reports
DO  - 10.1007/s13679-026-00728-1
UR  - https://doi.org/10.1007/s13679-026-00728-1
AB  - PURPOSEOF REVIEW: Ghrelin is a gut-derived acylated hormone that regulates appetite, food reward-related behaviours, glycaemic control, and lipid metabolism. These actions are primarily mediated through activation of the growth hormone secretagogue receptor (GHSR), which is highly expressed in the brain and also present in key metabolic organs. Ghrelin acylation by ghrelin O-acyltransferase (GOAT) is required for receptor binding and biological activity. This review examines the physiological and pathophysiological roles of ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), with particular emphasis on its relevance to obesity and type 2 diabetes. RECENT FINDINGS: LEAP2 has recently been identified as an endogenous antagonist and inverse agonist of GHSR that counteracts ghrelin signalling. Emerging evidence indicates that obesity and type 2 diabetes are generally associated with reduced circulating ghrelin levels and increased LEAP2 concentrations, particularly in the presence of insulin resistance. These reciprocal changes support the concept that the ghrelin/LEAP2 ratio functions as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, and may influence metabolic responses to nutritional status and weight loss. The ghrelin-LEAP2 system represents a key regulatory pathway in metabolic homeostasis and a promising therapeutic target for obesity and related metabolic disorders. Pharmacological strategies targeting this axis, including ghrelin antagonists, LEAP2 analogues, GOAT inhibitors, and GHSR inverse agonists, are under active investigation, although further studies are required to establish their long-term efficacy and safety.
SN  - 2162-4968
ER  -