Potential role of the pancreatic hormone insulin in resetting human peripheral clocks

Mammalian circadian rhythms are phase-adjusted and amplified by external cues such as light and food. While the light input pathway via the central clock, the suprachiasmatic nucleus, has been well defined, the mechanism of feeding-induced circadian resetting remains undefined, particularly in humans. Animal studies have indicated that insulin, a pancreatic hormone that is secreted rapidly in response to feeding, is an input factor for a few peripheral clocks, such as liver and adipose tissue. In this study, using plucked and cultured hair follicles as a representative human peripheral clock, we examined the effect of insulin on circadian characteristics of clock gene expression. Our results demonstrate that insulin phase-shifts or amplifies the clock gene expression rhythms of ex vivo cultured hair follicles in a phase-responsive manner. To reduce the possibility that differences in species, genetic or environmental background, and experimental methods affected experimental outcomes, we also treated surgically extracted whisker follicles of Period2::Luciferase (Per2(Luc)) mice with insulin and found that the effect of insulin on clock gene expression was reproducible. These results suggest the possibility that feeding-induced insulin resets peripheral circadian clocks in humans.