Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, 76100, Rehovot, Israel.
Plant Foods Hum Nutr. 2022 Mar;77(1):128-134. doi: 10.1007/s11130-022-00954-7. Epub 2022 Feb 18.
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.
白藜芦醇是一种具有代谢和昼夜节律作用的营养物质。虽然一些研究表明白藜芦醇与减少糖异生之间存在相关性，但其他研究则提出相反的观点。我们的目的是研究白藜芦醇在昼夜节律钟周围的代谢作用，以便更准确地确定涉及的肝信号通路。用白藜芦醇处理 AML-12 肝细胞，并在昼夜周期内测量时钟和代谢标记物。用白藜芦醇处理的 AML-12 肝细胞显示出以下关键代谢因子的比例降低：磷酸化的 PP2A 与总 PP2A（pPP2A/PP2A）、pAKT/AKT、pFOXO1/FOXO1 和 pAMPK/AMPK，表明 AKT 和 AMPK 受到抑制，但 PP2A 和 FOXO1 被激活。此外，白藜芦醇处理后磷酸化 mTOR 的水平较低。磷酸烯醇丙酮酸羧激酶（PEPCK）的关键糖异生酶水平在白藜芦醇处理后显著升高。与 mTOR 活性降低一致，时钟转录因子 pBMAL1/BMAL1 的比值也降低。Bmal1mRNA 在 AML-12 肝细胞中强烈振荡，但白藜芦醇处理导致其相位提前并降低其幅度，类似于对 Srebp1c 和 Pgc1α mRNA 的影响。用白藜芦醇处理后，Bmal1、Sirt1 和 Srebp1c 的每日 mRNA 水平均显著升高。白藜芦醇改变代谢和时钟基因的昼夜节律表达，激活禁食状态并诱导 PP2A-FOXO1-PEPCK 途径。
