The Role of the Endocrine System in Feeding-Induced Tissue-Specific Circadian Entrainment

Abstract

The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type-dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding-mediated tissue-specific entrainment.

Forced rather than voluntary exercise entrains peripheral clocks via a corticosterone/noradrenaline increase in PER2::LUC mice

“…This suggests that similar and common signaling pathways might be involved in the entrainment of the peripheral clocks in mice undergoing restricted feeding and exercise. Insulin release and the insulin-induced phase shift may be involved in the restricted feeding-induced phase shift of the peripheral clocks27282943. In the current study, treadmill exercise under a 12 h restricted feeding schedule, during the nighttime, produces a phase advance similar to that observed in free-feeding conditions.…”

“…Scheduled 4 h restricted feeding for 2–7 days was shown to result in a phase advance and phase delay of the peripheral clock, when feeding time was set at daytime and nighttime, respectively42. Insulin release and insulin-induced phase shifts may also be involved in the restricted feeding-induced phase shift of the peripheral clock27282943. To exclude the possible effects of feeding and insulin release on the phase shift after exercise, treadmill exercise was applied at ZT4 for 1 h in mice with restricted feeding during ZT12–24 and serum insulin levels were measured.…”

“…Recent reports have demonstrated that insulin release is a critical step in the entrainment of the mouse peripheral clock by restricted feeding2627. Thus, insulin acts as an entrainment signal262829. However, the mechanisms of entrainment of the peripheral clock by scheduled exercise are not well understood.…”

Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver

“…Recent studies demonstrated that insulin signals promote the circadian rhythm and associated functional gene expression in peripheral tissues [16][17][18]. These results indicate that the development of insulin resistance may disrupt the circadian rhythm.…”

Circadian System and Glucose Metabolism: Implications for Physiology and Disease

“…Such internal misalignment may compromise glucose tolerance by disturbing the time-coordinated tissue functions. Furthermore, a number of studies proposed that feeding-related hormones, such as insulin [75], glucagon-like peptide-1 (GLP-1) [76], and oxyntomodulin [77], can act as entrainment signals for peripheral clocks. However, it is not known how these feeding-related entrainment signals interact with those controlled by central clock (body temperature, glucocorticoids, etc.…”