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Leucine increases SIRT1, prevents mitochondrial dysfunction

leucine sirt1

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#1 ta5

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Posted 27 October 2014 - 03:12 AM


How do we reconcile these positive effects of leucine with the evidence that it also decreases lifespan?
 
 
Am J Physiol Endocrinol Metab. 2012 Nov 15;303(10):E1234-44. 
Li H1, Xu M, Lee J, He C, Xie Z.
Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD(+) levels, which decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1α and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity.

 

PMID: 22967499

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#2 Jim Morrison

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Posted 28 October 2014 - 01:10 PM

I have been wondering about this paradox too... Leucine is the aa that is most potent in activating mTOR and activity in this pathway should decrease lifespan. Seems that the SRT induction one gets from Lecine can compensate sufficiently for the increased mTOR signaling. Still, it would be interesting to see the effects of a high leucine diet would be in combination with mTOR inhibition, e.g. rapamycin...


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#3 Skyguy2005

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Posted 30 October 2014 - 05:18 PM

I have been wondering about this paradox too... Leucine is the aa that is most potent in activating mTOR and activity in this pathway should decrease lifespan. Seems that the SRT induction one gets from Lecine can compensate sufficiently for the increased mTOR signaling. Still, it would be interesting to see the effects of a high leucine diet would be in combination with mTOR inhibition, e.g. rapamycin...

 

http://www.ncbi.nlm....pubmed/22028412

 

Maybe activating mTOR inhibits eNOS expression, and that's the reason for a reduced lifespan?

 

http://www.plosone.o...al.pone.0031155

 

"Calorie restriction (CR) extends lifespans of model organisms ranging from yeast to mammals [1][4], and many groups have focused on understanding how this dietary intervention acts mechanistically. In 2005, Nisoli and collaborators [5] elegantly demonstrated that dietary restriction induced the activation of endothelial nitric oxide synthase (eNOS) and lead to enhanced mitochondrial biogenesis and increased oxygen consumption. Indeed, the effects of the diet were largely absent in eNOS deficient animals [5]. Further studies have found links between mitochondrial activity and CR. Fungal CR models present increments in respiratory activity [6][8], and CR in yeast can be promoted by NO-stimulated mitochondrial biogenesis [9]. Furthermore, CR prevents the decline in respiratory activity seen in aging rats [10], [11] and increasing respiratory activity through the use of mitochondrial uncouplers enhances mouse lifespan [12]. Interestingly, both CR and uncouplers enhance mitochondrial biogenesis in insulin-sensitive tissues, in a manner involving protein kinase B (Akt) phosphorylation [13]."

 

Rapamycin, Resveratrol, Ginkgo Biloba all act on eNOS.


Edited by Skyguy2005, 30 October 2014 - 05:30 PM.

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#4 ikon2

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Posted 05 December 2014 - 06:53 PM

I have been wondering about this paradox too... Leucine is the aa that is most potent in activating mTOR and activity in this pathway should decrease lifespan. Seems that the SRT induction one gets from Lecine can compensate sufficiently for the increased mTOR signaling. Still, it would be interesting to see the effects of a high leucine diet would be in combination with mTOR inhibition, e.g. rapamycin...

 

Or adding Reishi (cheaper alternative than Rapamycin).  I'll let you know how it works out as I'm doing it now ;)







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