Glucagon and/or IGF-1 Production Regulates Resetting of the Liver Circadian Clock in Response to a Protein or Amino Acid-only Diet

EBioMedicine. 2018 Feb:28:210-224. doi: 10.1016/j.ebiom.2018.01.012. Epub 2018 Jan 31.


The circadian system controls the behavior and multiple physiological functions. In mammals, the suprachiasmatic nucleus (SCN) acts as the master pacemaker and regulates the circadian clocks of peripheral tissues. The SCN receives information regarding the light-dark cycle and is thus synchronized to the external 24-hour environment. In contrast, peripheral clocks, such as the liver clock, receive information from the SCN and other factors; in particular, food intake which leads to insulin secretion induces strong entrainment of the liver clock. On the other hand, the liver clock of insulin-depleted mice treated with streptozotocin (STZ) has been shown to be entrained by scheduled feeding, suggesting that insulin is not necessary for entrainment of the liver clock by feeding. In this study, we aimed to elucidate additional mechanism on entraining liver clock by feeding a protein-only diet and/or amino-acid administration which does not increase insulin levels. We demonstrated that protein-only diet and cysteine administration elicit entrainment of the liver clock via glucagon secretion and/or insulin-like growth factors (IGF-1) production. Our findings suggest that glucagon and/or IGF-1 production are additional key factors in food-induced entrainment.

Keywords: Amino acid; Circadian rhythm; Food resetting; Glucagon; IGF-1; Protein.

MeSH terms

  • Animals
  • Circadian Clocks*
  • Cysteine / administration & dosage
  • Cysteine / pharmacology*
  • Diet*
  • Dietary Proteins / pharmacology*
  • Glucagon / biosynthesis*
  • Insulin-Like Growth Factor I / biosynthesis*
  • Liver / metabolism*
  • Mice, Inbred ICR
  • Podophyllin / pharmacology
  • Signal Transduction / drug effects
  • Streptozocin


  • Dietary Proteins
  • Streptozocin
  • Insulin-Like Growth Factor I
  • Podophyllin
  • Glucagon
  • Cysteine