Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock
Jiameng Sun,
Yiming Zhang,
Joshua A. Adams,
Cassandra B. Higgins,
Shannon C. Kelly,
Hao Zhang,
Kevin Y. Cho,
Ulysses G. Johnson,
Benjamin M. Swarts,
Shun-Ichi Wada,
Gary J. Patti,
Leah P. Shriver,
Brian N. Finck,
Erik D. Herzog,
Brian J. DeBosch
Affiliations
Jiameng Sun
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Yiming Zhang
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Joshua A. Adams
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Cassandra B. Higgins
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Shannon C. Kelly
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Hao Zhang
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Kevin Y. Cho
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Ulysses G. Johnson
Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA; Biochemistry, Cellular, and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI, USA
Benjamin M. Swarts
Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA; Biochemistry, Cellular, and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI, USA
Shun-Ichi Wada
Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
Gary J. Patti
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Leah P. Shriver
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Brian N. Finck
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Erik D. Herzog
Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, USA
Brian J. DeBosch
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: 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.
