Liraglutide protects β-cell function by reversing histone modification of Pdx-1 proximal promoter in catch-up growth male rats

Abstract

AimsCatch-up growth after a period of nutritional deprivation in adulthood is related to the onset of metabolic disorders. This process involves chromatin remodelling of the Pdx-1 gene in pancreas. The objective of this study was to determine the chromatin remodelling mechanism of GLP-1 analogue Liraglutide upon Pdx-1 in catch-up growth rats in vivo and in vitro. MethodsFive-week-old male specific pathogen free (SPF) Wistar rats were randomly divided into normal group, catch-up growth group and Liraglutide group. Hyperglycemic clamp test and glucose-stimulated insulin secretion test were carried out to evaluate β-cell function in vivo and in vitro. The histone H3 modification changes at the Pdx-1 proximal promoter were assessed by chromatin immunoprecipitation. ResultsThe catch-up growth state was characterized by less recruitment of histone H3 lysine4 trimethylation and histone H3 acetylation and more recruitment of histone H3 lysine9 dimethylation at the Pdx-1 proximal promoter. Liraglutide treatment reversed these epigenetic changes and increased Pdx-1 expression, which could be abrogated by GLP-1 receptor antagonist Exendin 9-39. The β-cell function of catch-up growth rats was improved after Liraglutide treatment. ConclusionsThe protective effects of Liraglutide on pancreatic islet β-cell function may be related to histone H3 modification at the Pdx-1 proximal promoter during catch-up growth and could be used to treat catch-up growth-related metabolic disorders.