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

• A peptide inhibitor of insulin attenuates feeding-induced circadian phase adjustment
• Insulin-induced phase shift in peripheral clocks is dependent on tissue type
• Transient activation of Per2 is sufficient for phase-dependent circadian shifts
• Circadian entrainment in insulin-sensitive tissues involves PI3K and MAPK pathways

SummaryThe 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.

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