Exendin-4 dosing time-dependently affects hepatic circadian clock through GLP-1 receptors in the central nervous system

Abstract

Aim To investigate the influence of dosing time and the role of glucagon-like peptide-1 receptor (GLP-1r) in the central nervous system (CNS) on the hepatic clock-modulating effect of exendin-4 (Exe-4). Methods Male B6 mice and CNS-specific GLP-1r knockout mice were maintained under a 12 h/12 h light/dark cycle, with 4-h time restricted feeding (TRF) or daytime-feeding (DF). Exe-4 or vehicle was administered repeatedly at the beginning of the active phase (ZT12) or rest phase (ZT0) for 4 or 5 days. After the last dosing, liver samples were collected every 6 h for measuring mRNA expression levels of the clock genes. Results The DF induced a substantial phase shift of the hepatic clock, and Exe-4 administered at ZT12 almost completely inhibited this effect of DF. On the other hand, Exe-4 administered at ZT0 had a minimal effect on the DF-induced phase shift, but enhanced the amplitude of hepatic clock. Under the TRF condition, Exe-4 did not affect the phase of the hepatic circadian clocks regardless of the dosing time. In the CNS-specific GLP-1r knockout mice, the counteracting effect of Exe-4 on DF-induced phase shift disappeared. Conclusion These results indicate that the effect of Exe-4 on the hepatic clock is dosing time-dependent and mediated by GLP-1r in CNS.