Resveratrol Induces the Fasting State and Alters Circadian Metabolism in Hepatocytes

Opal Chatam, Nava Chapnik, Oren Froy

Research output: Contribution to journalArticlepeer-review


Resveratrol is a nutritional substance that has both metabolic and circadian effects. While some studies indicate a correlation between resveratrol and reduced gluconeogenesis, others propose the opposite. Our aim was to study the metabolic effect of resveratrol around the circadian clock in order to determine more accurately the hepatic signaling pathways involved. AML-12 hepatocytes were treated with resveratrol and clock and metabolic markers were measured around the clock. Resveratrol-treated AML-12 hepatocytes showed reduced ratio of the following key metabolic factors: phosphorylated PP2A to total PP2A (pPP2A/PP2A), pAKT/AKT, pFOXO1/FOXO1 and pAMPK/AMPK, indicating inhibition of AKT and AMPK, but activation of PP2A and FOXO1. In addition, the levels of phosphorylated mTOR were low after resveratrol treatment. The levels of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were significantly higher after resveratrol treatment. In accordance with the reduced mTOR activity, the ratio of pBMAL1/BMAL1, the clock transcription factor, also decreased. Bmal1 mRNA oscillated robustly in AML-12 hepatocytes, but resveratrol treatment led to a phase advance and a decrease in its amplitude, similarly to the effect on Srebp1c and Pgc1α mRNA. After resveratrol treatment, daily mRNA levels of Bmal1, Sirt1 and Srebp1c were significantly higher. Resveratrol changes the circadian expression of metabolic and clock genes activating the fasting state and inducing the PP2A-FOXO1-PEPCK pathway.

Original languageAmerican English
Pages (from-to)128-134
Number of pages7
JournalPlant Foods for Human Nutrition
Issue number1
Early online date18 Feb 2022
StatePublished - Mar 2022


  • Circadian
  • Clock
  • Gluconeogenesis
  • Liver
  • Metabolism
  • PP2A
  • Resveratrol
  • Fasting
  • Humans
  • ARNTL Transcription Factors/genetics
  • Proto-Oncogene Proteins c-akt/metabolism
  • TOR Serine-Threonine Kinases/genetics
  • Leukemia, Myeloid, Acute/metabolism
  • Hepatocytes/metabolism
  • Resveratrol/metabolism
  • AMP-Activated Protein Kinases/metabolism
  • RNA, Messenger

All Science Journal Classification (ASJC) codes

  • Chemistry (miscellaneous)
  • Food Science


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