Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock

Hepatocyte Period 1 (Per1) is selectively induced during fasting, and mice lacking Per1 fail to initiate key metabolic processes.

• Mice without hepatocyte Per1 do not initiate autophagic flux, ketogenesis, or lipid accumulation during fasting.
• Transcriptomic analyses reveal a failure to induce the fasting hepatokine Fgf21 in Per1-deficient mice.
• Single-nucleus sequencing identifies a hepatocyte subpopulation that does not activate chromatin accessibility near the Fgf21 gene.
• Isotopic tracing and calorimetry show that Per1-deficient mice cannot switch from using glucose to fat for energy.
• The inability to transition to fat oxidation in Per1-deficient mice can be reversed by administering exogenous FGF21 or inhibiting pyruvate dehydrogenase.
• Other core circadian genes do not affect the induction of Per1 during fasting.

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