AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol

Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Diabetes (Impact Factor: 8.1). 11/2009; 59(3):554-63. DOI: 10.2337/db09-0482
Source: PubMed


Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or -alpha2 to determine whether the metabolic effects of resveratrol are mediated by AMPK.
Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro.
Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1(-/-) mice. In the absence of either AMPKalpha1 or -alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly.
We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.

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    • "Moreover, RESV, per se, is a powerful oxidant that in a moderate to high μM range (N 50 μM) was shown to activate AMPK in a SIRT1-independent manner, improving mitochondrial function and, consequently, neuronal survival [6] (Fig. 1). Likewise, RESV failed to improve metabolic parameters and mitochondrial biogenesis in AMPKα1 subunit KO mice [78], revealing an important role of this kinase regulated under conditions favoring ATP metabolism. Concordantly, high doses of RESV improved neuronal survival in Sir2 homozygous null flies expressing mHtt exon 1 with 93Q (Httex1pQ93) [58]. "
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    • "Indeed, Roberts reported that fetal pancreatic development was altered in resveratrol-supplemented pregnancies which may have negative effects on metabolism later in life [27]. The metabolic effects of resveratrol have been shown to depend upon activation of AMPK [28]. Indeed, we demonstrated in our model that chronic resveratrol supplementation of HFD prior to and during pregnancy was associated with 22-fold higher levels of phosphorylated AMPK in the placenta as compared to HFD alone. "
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    • "Earlier reports established that RSV acted through direct activation of SIRT1 (Howitz et al., 2003); however, a more recent study proposed an indirect modulation of SIRT1 via inhibition of cAMP phosphodiesterases (Park et al., 2012). Nevertheless, the preponderance of evidences indicates that RSV activates SIRT1 through direct and indirect actions (Canto et al., 2010; Um et al., 2010) and that the metabolic effects of RSV depend on acute activation of AMPK (Baur et al., 2006) via a SIRT1-independent mechanism (Price et al., 2012). "
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