Refeeding after Fasting Elicits Insulin-Dependent Regulation of Per2 and Rev-erbα with Shifts in the Liver Clock

Abstract

The mammalian circadian clock is known to be entrained by both a daily light-dark cycle and daily feeding cycle. However, the mechanisms of feeding-induced entrainment are not as fully understood as those of light entrainment. To elucidate the first step of entrainment of the liver clock, we identified the circadian clock gene(s) that show both phase advance and acute change of gene expression during the early term of the daytime refeeding schedule in mice. The expressions of liver Per2 and Rev-erbα genes were phase-advanced within 1 day of refeeding. Additionally, the upregulation of Per2 mRNA and down-regulation of Rev-erbα mRNA were induced within 2 hours, not only by food intake but also by insulin injection in intact mice. These expression changes by food intake were not revealed in streptozotocin-treated insulin-deficient mice, but insulin injection was able to recover the impairment of Per2 and Rev-erbα gene expression. Furthermore, we demonstrated using an ex vivo luciferase monitoring system that insulin injection during the daytime causes a phase advance of liver Per2 expression rhythm in Per2::luciferase knock-in mice. In embryonic fibroblasts from Per2::luciferase knock-in mice, insulin infusion caused an acute increase of Per2 gene expression and a similar phase advance of Per2 expression rhythm. Our results indicate that an acute change of Per2 and Rev-erbα gene expression mediated by refeeding-induced insulin secretion is a critical step mediating the early phase of feeding-induced entrainment of the liver clock.

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

“…Finally, we also studied genes important for various metabolic processes: genes involved in the leptin signaling pathway, gluconeogenesis and lipid metabolism. Overall, the observed effect on the expression of these genes confirmed the effect of insulin at 0.5 hpi, for instance on per2 and pck1 which are known to be rapidly regulated by insulin in mammals (O'Brien & Granner 1990, Tahara et al 2011. The data also provide further evidence of the loss of insulin sensitivity at 4 hpi, as observed with lepb, lepr, gck, Transcriptome analysis and comparison of zebrafish larvae in an insulinsensitive state and insulin-resistant state.…”

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

“…The liver is considered a peripheral clock, in the sense that it can regulate various metabolic pathways depending on the expression of certain molecular clocks such as the PER and CRY family proteins (Sahar & Sassone-Corsi 2012). There is growing evidence of the reverse process, by which the metabolic state regulates PER2, which in turn controls hepatic glycogen storage/ degradation (Tahara et al 2011, Zani et al 2013. Supporting previous findings, per2 regulation may limit glucose production by increasing glycogen storage or preventing glycogenolysis in obese zebrafish.…”

Interactions between endocrine and circadian systems

“…But insulin can also feed back to the clock. Tahara et al (2011) used daytime RF in mice to demonstrate insulin-dependent alterations of clock gene rhythms in the liver, and a similar response was seen in primarily cultured rat hepatocytes (Yamajuku et al 2012). It would be remiss to discuss the effects of insulin on the clock without discussing the effects of glucose as a direct function of insulin signalling.…”