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AMPK is Primary Resveratrol Target


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#1 niner

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Posted 05 March 2010 - 03:28 PM


Diabetes. 2010 Mar;59(3):554-63. Epub 2009 Nov 23.
AMP-Activated Protein Kinase-Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol.
Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH.

Corresponding author: Jay H. Chung, chungj@nhlbi.nih.gov.

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

PMCID: PMC2828647 [Available on 2011/3/1]
PMID: 19934007

#2 malbecman

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Posted 05 March 2010 - 09:28 PM

Pretty interesting. Certainly would make sense given that AMPK is evolutionarily conserved across so many species. Either way, SIRT activation (now doubtful) or AMPK activation (which now appears more likely) is fine by me. :)

I wonder if resveratrol binding is a direct activation or allosteric activator?

Now I just need some purified AMPK and I can do some binding studies........

Thanks, Niner.

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#3 niner

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Posted 05 March 2010 - 10:24 PM

There's still the issue of the yeast sirt2 knockouts that obviate the effect of resveratrol. I suppose that means that sirtuins are on the critical pathway either upstream or downstream of AMPK as far as this type of signaling goes. How do we know that the "true target" is really AMPK? I don't have access to the paper at the moment, and haven't read it.

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#4 tunt01

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Posted 05 March 2010 - 10:58 PM

There's still the issue of the yeast sirt2 knockouts that obviate the effect of resveratrol. I suppose that means that sirtuins are on the critical pathway either upstream or downstream of AMPK as far as this type of signaling goes. How do we know that the "true target" is really AMPK? I don't have access to the paper at the moment, and haven't read it.



we actually came to this conclusion in a prior thread. find the thread that is titled: "what is resveratrols true target - nampt?". i think i posted in there i thought it was AMPK and NAMPT which catalyzed SIRT1 (downstream). geddarkstorm's made the original post.

EDIT:

This is the original thread

http://www.imminst.o...showtopic=27350

This was the post I made hypothesizing AMPK as the true target

http://www.imminst.o...&...st&p=306931

Edited by prophets, 05 March 2010 - 11:25 PM.





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