Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application

Abstract

Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol’s effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK. In this context, resveratrol activates SIRT1 (1) by directly binding to SIRT1; and (2) by increasing NAD+ levels by upregulating the salvage pathway through Nampt activation, an effect mediated by AMPK. The first mechanism promotes deacetylation of a limited number of SIRT1 substrate proteins (e.g., PGC-1). The second mechanism (which may be more important than the first) activates other sirtuins in addition to SIRT1, which affects a broad spectrum of substrates. Despite these findings, detailed mechanisms of how resveratrol activates AMPK have not been reported. Here, we show that (1) resveratrol-induced activation of AMPK requires the presence of functional LKB1; (2) Resveratrol increases LKB1 activity, which involves translocation and phosphorylation at T336 and S428; (3) Activation of LKB1 causes proteasomal degradation of LKB1; (4) At high concentrations (50–100 µM), resveratrol also activates AMPK through increasing AMP levels; and (5) The above-mentioned activation mechanisms vary among cell types, and in some cell types, resveratrol fails to activate AMPK. These results suggest that resveratrol-induced activation of AMPK is not a ubiquitous phenomenon. In addition, AMPK-mediated increases in NAD+ in the second mechanism require several ATPs, which may not be available in many pathological conditions. These phenomena may explain why resveratrol is not always consistently beneficial in a clinical setting.

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“…Disregarding this special effect, the insulin-sensitizing actions of resveratrol are complex and not completely elucidated. Part of the pharmacodynamic effects of this stilbene compound could derive from its capacity to modulate different pathways and molecular targets, including those downstream of the insulin receptor and mediated by AMP-activated protein kinase (AMPK) and sirtuin 1, as reported in clinical studies on diabetic patients and rodent models of IR, as well as in vitro experimental settings [147][148][149][150][151]. In these studies, treatment with resveratrol has proved to activate both fuel-sensors AMPK and sirtuin 1 in insulin-sensitive peripheral tissues, especially skeletal muscles.…”

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“…AMPK phosphorylation by metformin and statins may be independent of the cellular ATP to AMP ratio [70], though the exact mechanism is unclear. Resveratrol, a polyphenolic anti-oxidant, has been shown to activate AMPK by both changing the cellular energy state and by activating its upstream kinase, LKB1, through deacetylation by sirtuin 1 [71]. The tissue ATP to AMP ratio can also be reduced by the PPARγ agonists, namely the antidiabetic thiazolidinediones, which activates AMPK allosterically through increased levels of AMP [72].…”

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“…Resveratrol, a phytochemical found in the skin of grapes and various berries, also activates AMPK via two mechanisms. It inhibits ATP-synthase, increasing the ratio of AMP to ATP, and also stimulates SIRT1-mediated deacetylation of LKB1, thereby increasing AMPK activity [53]. AMPK and SIRT1 have an important reciprocal relationship that is critical for many of their downstream effects [54].…”

“…Variables such as cell type, bioenergetic status, the specific cellular stressors (including baseline cellular stress), and the length and intensity of AMPK activation are all likely relevant factors [48,53]. For example, the relationship between AMPK activity and cell death under some conditions may be biphasic, such that at certain levels AMPK activation promotes cell survival, but at higher intensities or over a longer duration it promotes PCD [155].…”