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LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging.
Life Sci. 388:124219 (2026)
SCOPE: Global increase in obesity and metabolic syndrome has led to a marked rise in comorbidities, with liver disease emerging as a major concern. Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over 30% of the population, making it the most prevalent liver disorder worldwide. Hepatic steatosis, hallmark of MAFLD, can progress to inflammation, fibrosis, steatohepatitis, and cirrhosis. Despite advances in elucidating its mechanisms, no effective pharmacological therapy exists to reverse disease progression. Ghrelin signaling axis has been implicated in energy and lipid homeostasis, and the recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous ghrelin receptor antagonist and inverse agonist has generated interest in its potential role in liver metabolism. The primary objective of this study was to evaluate LEAP2 on hepatocyte lipid metabolism and determine its capacity to prevent diet- and age-induced steatosis in vivo. METHODS AND RESULTS: We investigated LEAP2 actions on hepatocyte lipid metabolism using human and mouse hepatocyte cultures, also we did in vivo studies in mice with chronic central LEAP2 administration in models of diet-induced and age-related steatosis. LEAP2 inhibited lipid accumulation in hepatocytes and reduced hepatic lipid deposition in mice fed a standard diet. However, LEAP2 did not prevent high-fat diet-induced steatosis in young mice although it attenuated hepatic inflammation. In aged animals, LEAP2 failed to suppress age-associated inflammation and steatosis. CONCLUSION: LEAP2 has been identified as a novel regulator of hepatic lipid metabolism with the potential to counteract inflammation-associated steatosis, although its effects on age-related steatosis appear limited. Targeting the LEAP2-ghrelin axis may represent a promising therapeutic strategy; however, further studies are required to determine its efficacy in diet-induced hepatic disease.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Ghrelin ; Leap2 ; Aging ; High Fat Diet ; Liver ; Obesity ; Steatosis; Hormone Secretagogue Receptor; Des-acyl Ghrelin; Nonalcoholic Steatohepatitis; Food-intake; Activation; Peptide; Liver; Mtor; Acyltransferase; Metabolism
ISSN (print) / ISBN
0024-3205
e-ISSN
1879-0631
Journal
Life Sciences
Quellenangaben
Volume: 388,
Article Number: 124219
Publisher
Elsevier
Publishing Place
The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)
Grants
Ministerio de Ciencia, Innovacion y Universidades
European Union
Conselleria de Educacion, Ciencia, Universidades e Formacion profesional da Xunta de Galicia (Singular Research Centre accreditation)
FEDER funds
CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain
European Union
Conselleria de Educacion, Ciencia, Universidades e Formacion profesional da Xunta de Galicia (Singular Research Centre accreditation)
FEDER funds
CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain