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

Abstract

OBJECTIVEResveratrol, 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 AMPKα1 or -α2 to determine whether the metabolic effects of resveratrol are mediated by AMPK.RESEARCH DESIGN AND METHODSMice deficient in the catalytic subunit of AMPK (α1 or α2) 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.RESULTSResveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKα1−/− mice. In the absence of either AMPKα1 or -α2, 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.CONCLUSIONSWe conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

“…In addition, AMPK, another SIRT1-interacting factor with a vital role in the regulation of hydrolysis and energy dissipation [27,28], was activated by exenatide in WAT. Our findings indicate that exenatide induces the phosphorylation of AMPK which, in turn, activates SIRT1 by regulating NAD + concentration [29], triggering a lipolytic cycle.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Resveratrol found in red grape skin is a potent antioxidant that has been shown to reduce amyloid plaque burden and improve memory deficits in transgenic AD mouse models [132,133]. Resveratrol activates the 5'adenosine monophosphate-activated protein kinase pathway, and stimulates activity of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 [134,135], which subsequently activates the PGC1α metabolic regulatory pathway and promotes mitochondrial biogenesis [136][137][138][139]. Several clinical trials are currently underway to investigate the efficacy of resveratrol, including a Phase II trial on mild-to-moderate AD (ClinicalTrials.gov identifier: NCT01504854), a Phase III on mild-to-moderate AD (ClinicalTrials.gov identifier: NCT00743743), and a Phase IV on MCI, which combines resveratrol with omega-3 (ClinicalTrials.gov identifier: NCT01219244).…”

“…Latrepirdine is proposed to interact with glutamate Reduces oxidative stress, reduces amyloid plaques, improves memory deficits in transgenic mouse models of AD No major effect on cognitive function [132][133][134][135][136][137][138][139] AD = Alzheimer's disease; ROS = reactive oxygen species; SOD = superoxide dismutase; MitoQ = mitoquinone mesylate; AMPK = adenosine monophosphate-activated protein kinase; NAD = nicotinamide adenine dinucleotide; SIRT1 = sirtuin 1 receptors, block voltage-dependent calcium channels, and inhibit mitochondrial permeability, thereby suppressing unnecessary mitophagy or apoptosis [153,154]. In a Phase II clinical trial in patients with moderate AD, it significantly improved cognitive function over placebo [155].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…AMPK and SIRT1 apparently regulate each other and share common target molecules. AMPK could be upstream of SIRT1, that is, regulate SIRT1 activity (Canto et al 2010;Um et al 2010), thus controlling SIRT1-mediated effects on aging and health. In addition, due to its interaction with cryptochrome 1, a component of circadian clock in peripheral tissues, AMPK contributes to metabolic entrainment of peripheral clocks (Lamia et al 2009).…”

“…For example, leptin activates AMPK in adipose tissue, SM, and liver but inhibits it in hypothalamus (Lim et al 2010), while adiponectin and anti-diabetic drugs primarily activate the AMPK in the peripheral tissues. Furthermore, there is a number of natural food components believed to exert beneficial effects on health in association with activation of AMPK like plant polyphenols (Um et al 2010) or n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) (Jelenik et al 2010;Kopecky et al 2009). The role of AMPK in energy metabolism has been most intensively studied in SM, heart, adipose tissue, liver, beta cells, and hypothalamus, that is, tissues that are highly sensitive to changes in energy balance and also actively involved in its regulation.…”