|Image 1: The quest for fat loss, muscle size, health and longevity reminds me of the famous egg-laying wool-milk-sow. |
When AMPK is the good guy, mTOR must not necessary be the bad guy
We have learned in the past couple of installments that its modulatory effect on the AMPK/mTOR seesaw, which, even in your average citizen of the affluent Western hemisphere, is oftentimes imbalanced towards the "anabolic" mTOR side, these days. Against that background I have pointed towards the myriad of beneficial metabolic effects of AMPK activation, which could in fact ameliorate, if not reverse, many of the ailments that have befallen our fat-anabolic (remember without mTOR, fat cells cannot differentiate, cf. Bell. 2000, where blockage of the mTOR pathway with rapamycin inhibited adipocyte differentiation) society.
|Illustration 1: Lifestyle factors like nutrition, nutrient timing, sleep etc. determine the fundamental balance between AMPK and mTOR, but supps can skew / tweak the balance|
|Image 2: A breast cancer cell (img from The Guardian); if you want it (not yourselves!) to live longer, don't feed it with leucine, Ladies!|
As induction of apoptosis rather than cytostasis is increasingly considered a prerequisite for an effective anticancer agent, it will be crucial to understand when rapamycin has such effects and where it does not, and to learn how to trigger apoptosis with additional therapies.Now, the use of novel pharmacological mTOR-inhibitors aside, any dietary approach (such as leucine deprivation) would obviously prevent apoptosis, because it would act via mTORC1 inhibition to increase Akt-expression and (cancer-)cell survival (Sun. 2005; O'Reilly. 2005). Would you risk your "metabolic currency", i.e. your muscle, and sacrifice quality of life for the futile hope that you could thusly keep cancer "at bay"? I hope not, because in that case you still have not grasped the fundamental idea that in life its not about black and white, but about black and white and a balance between the two.
When to take what to optimize fat loss and minimize muscle loss in the AMPK phase
In the comments related to the last installment, Bomb Jack suggested that taking ALA during a fast to jack the naturally high AMPK level up even more, would theoretically make sense, but he mentions that he had seen "studies about [ALA] causing lean tissue loss on the long run". One of these studies was conducted by Yi Wang et al. in 2010 on 24 month old male C57BL/6 mice (Wang. 2010). Half of the mice received 0.75% alpha-lipoic acid in their drinking water for one month, the rest of the mice served as a unsupplemented control.
|Image 3: 22 month old C57BL/6 mouse, in view of the fact that mice live ~2.5 years this is already a granny; in other words, the 24 month old mice in the Wang study were really old.|
- food consumption decreased: -18% - 4.50 ± 0.30 g/d vs. 5.50 ± 0.30 g/d in control mice
- body weight decreased: -15.8% - 5.27 ± 0.62 g total body weight loss
- energy expenditure increased: +25% - 7.64 ± 0.10 kcal/kg0.75/h vs. 5.90 ± 0.10 kcal/kg0.75/h
- glucose utilization increased: +10% judged by the respiratory quotient
- insulin sensitivity increased: -47% area under the curve in glucose tolerance test
- mitochondrial biogenesis increased: +138% relative abundance of mtDNA content
- PGC-1α* in skeletal muscle increased: + 80.0%
- GLUT-4 in skeletal muscle increased: + 105.0%
* PGC-1α ramps up thermogenesis, stimulates mitochondrial biogenesis, promotes the remodeling of muscle tissue, controls lipid and glucose metabolism (Liang. 2006)
|Figure 1: Relative changes in phosphorylation status of AMPK, mTOR, p70S6K and 4E-BP1 in old mice supplemented with 0.75% ALA in their drinking water for 1 month compared to unsupplemented control (data calculated based on Wang. 2010)|
|Figure 2: Absolute (left) and relative (right) changes in body composition in old mice supplemented with 0.75% ALA in their drinking water for 1 month compared to unsupplemented control (data calculated based on Wang. 2010)|
Rythmicity is the key when it comes to seesawing and supplementation
The mouse vs. human issue aside, the Wang study has another caveat in terms of drawing conclusions regarding the use of ALA and other AMPK promoters during an intermittent fast - the mice did not fast ;-) Reason would dictate, though, that ingesting ALA with drinking water 24/7 on a dietary regimen with constant food availability would actually be a disadvantage compared to taking ALA specifically at the onset of the fast (i.e. when your last meal would be digested) to keep AMPK, which would already been raising at that point (and thus mTOR declining) maximized in the course of the fasting period. On the other hand, taking ALA or any other AMPK promoter after your workout and before your meal would appear to be plain out stupid, as intermittent fasting does only make sense if you really reap the maximal anabolic benefit from the short feeding window. Against that background, popping alpha lipoic acid post workout and thus potentially increasing AMPK appears (remember that we do not have any studies explicitly investigating the effects of taking ALA post-workout vs. at other times of the day, so that these are just yet to be validated hypotheses!) to be counter-indicated, as it would potentially blunt the mTOR and p70S6K response to exercise and food-intake.
|Image 2: R- and S- isomer of alpha lipoic acid (Shay. 2010)|
I mean we all "know" that R-ALA is the preferable form, but do you remember where you know that from?
Well, me neither and so I dug back into the host of studies BASF was doing back in the 1990s, until their business department finally realized that a natural anti-diabetes drug is not only non-patentable, but could also compromise the sales of patentable pharmacological drugs like Chlorpropamide (patented in the mid-1980s; cf. DrugPatentWatch) which happens to be made of Propylamine, which in turn - you guessed it - is produced by BASF and sold to BigPharma and the Agrobusiness who use the same ingredient to produce of Prochloraz, and other well-known fungicide... but I am getting taken away, here.
|Image 2: The scientific |
evidence pro R-ALA
is quite conclusive;
the S-isomer, however,
could potentially negate
its benefits and is
useless, at best!
The "hungry" side of neuronal AMPK activation
Before I end, this pretty epic (in terms of the details we have covered) yet not very productive (in terms of how much ground we have made) installment of the Intermittent Thoughts, I want to briefly mention a very important and actually completely logical, since natural difference between the effects of increased AMPK phosphorylation in skeletal muscle and increased AMPK phosphorylation in the brain. While the former triggers all the fat-loss friendly adaptations you read about in this, as well as in previous Intermittent Thoughts, the later will have you forage through your fridge in no time - regardless of whether it's feeding time or not ;-)
|Illustration 2: The differential role of hypothalamic, liver and skeletal muscle AMPK expression (Long. 2006)|
- an increase in cerebral AMPK phosphorylation results in increased food intake (Andersson. 2004), while dephosphorylation decreases food intake (Kim. 2004);
- genetically modified mice with no AMPK activity in the AgRP neurons were leaner and had an increased energy expenditure compared to wild-type mice (Claret. 2007)
- ghrelin, the hunger hormone, triggers AMPK phosphorylation in the brain and thus increases food intake (Kola. 2008)
Update (10/29/2011) - The two AMPK-isoforms: As Mounier et al. report in a very recent paper the two isoforms of AMPK, i.e. AMPKα1 and AMPKα2 have very distinct effects on the mTOR induced increase in muscle protein synthesis, and thusly, muscle size (Mounier. 2011). As the scientists point out, AMPKα1 plays "a predominant role in the control of muscle cell size" (meaning it prevents exuberant hypertrophy), while AMPKα2 mediates "muscle metabolic adaptation" (increased glucose uptake, mitochondrial biogenesis, etc.), of which we have learned that they are so vital for our metabolic health.
Close your eyes and lean out
On that note, I will close today's lesson with an some interesting information from a study Jonathan P. has brought back onto my radar, recently. It's a study by Dworak et al. on ATP changes during sleep (Dworak. 2010), which underlines the importance of sleep, specifically when you want to lose weight, because at the onset of sleep, the reduction in neuronal activity goes hand in hand with a surge in brain ATP levels, which (as you have learned today) will reduce cerebral AMPK phosphorylation and its negative metabolic consequences. Prolonged waking, on the other hand, has been shown to increase AMPK activity in the brain (Wigren. 2009). So, what are you waiting for? That's all for today... lights out ;-)!