Peptides. 2025 Jul 3:171427. doi: 10.1016/j.peptides.2025.171427. Online ahead of print.
ABSTRACT
OBJECTIVE: The study aimed to investigate the possible effect of central unacylated ghrelin (UAG) on metabolic associated fatty liver disease (MAFLD) and its underlying mechanism.
METHODS: A high fat diet (HFD) was fed to rat to construct MAFLD model. UAG was administered via intra-cerebroventricular injection (ICV) and its effect on MAFLD was observed. Glucagon-like peptide-1 (GLP-1) neural pathway was observed via FluoroGold (FG) retrograde tracking combined with immunofluorescence. To assess the involvement of the GLP-1 pathway, GLP-1 receptor (GLP-1R) inhibitor Exendin (9-39) was injected prior to ICV of UAG.
RESULTS: ICV administration of UAG significantly reduced lipid accumulation in liver and liver injury in MAFLD rats which was partially attenuated by Exendin(9-39). Central UAG upregulated and activated GLP-1 neurons in nucleus tractus solitarii (NTS), and increased GLP-1 projections from NTS to paraventricular hypothalamic nucleus (PVN) and ventral tegmental area (VTA), respectively. Consequently, GLP-1R in PVN and VTA was activated, resulting in decreased food intake and reward behavior, as well as increased hepatic insulin sensitivity via activation of IRS-1/PI3K/Akt signaling pathway. These changes downregulated key lipogenic enzymes, including fatty acid synthase (FAS), acetyl-CoA Carboxylase (ACC) and stearoyl-CoAdesaturase-1 (SCD-1), thereby alleviating MAFLD.
CONCLUSION: These findings suggest that central UAG might alleviate MAFLD by modulating GLP-1 neuronal pathway from NTS to PVN and VTA. Further studies are needed to identify the specific receptor for UAG and its potential interaction with GLP-1 or GLP-1R, which could provide direct evidence for the role of central UAG in regulating food intake and lipid metabolism in MAFLD.
PMID:40617328 | DOI:10.1016/j.peptides.2025.171427