AMP‐activated protein kinase mediates the antioxidant effects of resveratrol through regulation of the transcription factor FoxO1

Abstract

Numerous physiological functions are controlled by redox-responsive signaling pathways. Disruption of redox balance by oxidative stress is recognized as a major cause of many pathological conditions, including aging, highlighting the importance of investigating how antioxidants maintain redox homeostasis. AMP-activated protein kinase (AMPK) is activated in response to cellular conditions that accompany energy depletion and plays a central role in the regulation of energy homeostasis, tumorigenesis and longevity. Recently, several antioxidants have been reported to activate AMPK, although the mechanisms by which AMPK acts to adjust the levels of cellular reactive oxygen species are not fully characterized. In the present study, we investigated the role of AMPK in mediating resveratrolinduced antioxidant effects and the molecular mechanisms underlying its actions. We demonstrate that AMPK activity plays an indispensable role in the operation of the ROS defense system by inducing the expression of the antioxidant enzymes, manganese superoxide dismutase and catalase, in response to resveratrol or the AMPK agonist 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleotide. In addition, we identified the mechanism involved in the antioxidant function of AMPK, demonstrating that AMPK directly phosphorylates human FoxO1 (forkhead box O1) at Thr 649 in vitro and increases FoxO1-dependent transcription of manganese superoxide dismutase and catalase. Mutagenesis studies showed that this AMPK-mediated phosphorylation of FoxO1 is critical for FoxO1 stability and nuclear localization, establishing the molecular basis for the induction of FoxO1 transcriptional activity. Our results reveal a novel FoxO1-dependent mechanism by which AMPK controls the expression of antioxidant enzymes and suggest that AMPK has an important role in maintaining redox homeostasis.Abbreviations ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleotide; AMPK, AMP-activated protein kinase; BS-mut, binding site mutation; CaMKKb, calcium/calmodulin-dependent protein kinase kinase b; CuZnSOD, copper zinc superoxide dismutase; FACS, fluorescence-activated cell sorting; FHRE, forkhead response element; FOXO, forkhead box O; GFP, green fluorescent protein; GPx, glutathione peroxidase; GST, glutathione S-transferase; HRP, horseradish peroxidase; MnSOD, manganese superoxide dismutase; ROS, reactive oxygen species; WT, wild-type.

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

“…The relationship between AMPK and cellular senescence/aging has been suggested (Stenesen et al ., 2013; Ido et al ., 2015), and the role of AMPK in aging prevention is generally attributed to its effects on the activation of Sirt1 and FoxO1 (Wang et al ., 2011; Yun et al ., 2014), as well as the suppression of mTOR (Salminen & Kaarniranta, 2012). However, in the level of cellular aging, contradictory findings exist (Lee et al ., 2015).…”

Post-translational modifications of FOXO family proteins

“…AMPK activity is necessary for defending against ROS-induced injury, and the molecular mechanism responsible for this effect. AMPK directly phosphorylates human FOXO1 at Thr649, which is critical for FOXO1 nuclear localization, stabilization and transcriptional activity, and the phosphorylation event leads to increased expression of the anti-oxidant enzymes, manganese superoxide dismutase (MnSOD) and catalase (57).…”

Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway

“…Dietary vitamin E and C supplementation attenuated glucose intolerance in rats by AMPK activation in muscle [47]. Polyphenols such as resveratrol have been reported to activate the AMPK signaling pathway [48]. Therefore, water soluble dietary fiber as well as antioxidants such as vitamin c and polyphenols/flavonoids, exist in OFS extract and might play role in intestinal glucose absorption, glucose uptake to peripheral tissues, and improvement of insulin action in this study.…”