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Resveratrol Induces the Fasting State and Alters Circadian Metabolism in Hepatocytes

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Abstract

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.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AKT:

Protein kinase B

AMPK:

AMP-activated protein kinase

Bmal1:

Brain and muscle Arnt-like protein-1

cAMP:

Cyclic AMP

Clock:

Circadian locomotor output cycles kaput

Cry:

Cryptochrome

PDE:

Phosphodiesterase

PEPCK:

Phosphoenolpyruvate carboxykinase

Per:

Period

PKA:

Protein kinase A

PP2A:

Protein phosphatase 2

SCN:

Suprachiasmatic nuclei

Sirt1:

Sirtuin 1

SREBP1c:

Sterol regulatory element-binding protein 1c

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Authors and Affiliations

  1. Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, 76100, Rehovot, Israel

    Opal Chatam, Nava Chapnik & Oren Froy

Authors
  1. Opal Chatam
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  2. Nava Chapnik
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  3. Oren Froy
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Contributions

O.C. and N.C. performed the experiments, cell collection and analyses. O.F. provided critical analyses of the data. O.C. wrote the first draft of the manuscript. O.F. extensively revised the manuscript.

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Correspondence to Oren Froy.

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Chatam, O., Chapnik, N. & Froy, O. Resveratrol Induces the Fasting State and Alters Circadian Metabolism in Hepatocytes. Plant Foods Hum Nutr 77, 128–134 (2022). https://doi.org/10.1007/s11130-022-00954-7

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