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

Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period 1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus. In vivo isotopic tracing and indirect calorimetry demonstrate that hepatocyte Per1-deficient mice fail to transit from oxidation of glucose to fat, which is completely reversible by exogenous FGF21 or by inhibiting pyruvate dehydrogenase. Strikingly, disturbing other core circadian genes does not perturb Per1 induction during fasting. We thus describe Per1 as an important mechanism by which hepatocytes integrate internal circadian rhythm and external nutrition signals to facilitate proper fuel utilization. [Display omitted] •Hepatocyte Per1 is induced by fasting independent of the core circadian clock•Hepatocyte Per1-deficient mice exhibit broadly defective fasting physiology•Per1 mediates fasting-induced Fgf21 and Pdk4 expression•FGF21 reconstitution and PDH inhibition rescue defective fasting metabolism In this paper, Sun et al. show that a core circadian gene, Period 1, is uniquely upregulated during fasting in liver. Mice lacking hepatocyte Per1 fail to oxidize glucose and fatty acid properly during fasting, a defect rescued by supplying FGF21 or inhibiting pyruvate dehydrogenase activity.