Sunday, September 25, 2011

Intermittent Thoughts on Intermittent Fasting - The Switch: Introducing the AMPK vs. mTOR Metabolic Seesaw

Figure 1: The mTOR - AMPK "cycle" can become a vicious one, as soon as its natural balance becomes disturbed by external, mostly nutritional and/or exercise related factors. Intermittent fasting could help you restore the balance.
Before we prematurely(?) break the fast and get to the nitty gritty of the feeding window, I want to briefly recapitulate the results of the last installment, which - as it will turn out - are of particular importance in view of today's discussion, as well. It were the thoughts on the health and possibly life-extending effects of intermittent fasting in the last installment of this series that brought up the involvement of 5'-adenosine monophospate (AMP)-activated protein kinase (AMPK) in both the weight, or we should say, fat loss and possible life-extending and anti-cancer effects of (intermittent) fasting. Now, before we even delve into a more detailed discussion of its relation to its "antagonist", the mammalian target of rapamyacin (mTOR), it would appear prudent to begin today's 6th installment of the Intermittent Thoughts on Intermittent Fasting series with a brief review of AMPK's effect(s) on protein synthesis, adipose tissue metabolism and apoptosis.

We already know that both fasting and exercise trigger increases in AMPK enzyme expression, which in and out of itself acts as an intracellular sensor that registers elevated AMP/adenosie tri-phospate (ATP) and inorganic phospate(Pi)/phosphocreatine (PCr) ratios - in short, it registers when you are running out of fuel. It is thus obvious that the main function of AMPK within muscle cells is to maintain energy stores at homeostatic levels. In order to achieve that, the 5’-adenosine monophosphate (AMP)-activated protein kinase enzyme upregulates catabolic processes and downregulates anabolic processes. The (entailing) overall effects the phosphorylation, i.e. the activation, of AMPK has on your metabolism are yet more complex than this dichotomous distinction would suggest - its tissue specific effects are illustrated in figure 2:
Figure 2: Downstream effects the "activation" of AMPK has on liver, muscle, and fat tissue.
In terms of the thought-after gain/retention of lean muscle mass, you must thusly consider AMPK as one of your worst enemies - an enemy which has conclusively been shown to respond to decreasing muscle glycogen content, both at rest and during exercise (Wojtaszewski. 2003) and inhibits overload-induced hypertrophy in fast-twitch muscle fibers.

Now, it would be paradigmatically short-sighted to draw the bro-scientific conclusion that you, as a physical culturist, should do everything in your power to avoid the phosphorylation of the 5’-adenosine monophosphate (AMP)-activated protein kinase enzyme to harness the power of permanent mTOR-activation. As mentioned in the last installment, AMPK and mTOR, i.e. the mammalian target or rapamycin, are antagonist - yet not in the sense of a switch with two mutually exclusive positions, but rather like two kids on a seesaw: where one can only go up, when the other is going down.

Proteine kinase seesawing for beginners

Image 1: Seesawing ain't working if you are trying to do it with someone who does not allow AMPK to come into it's own (img perceptasmile)
There is however more to this analogy than it may appear at first sight. If you think about your childhood, did you ever try to seesaw with an adult or another kid that was much heavier than you were? I assume if you have, you will remember that this was not very funny, because it constantly disrupted the natural (and fun) rythm of up and down... if you are asking yourself now, where this stupid physicist is heading with his seesaw example, think of your counterpart on the other side of the seesaw as being a sedentary, obese, carboholic diabetic who is constantly stuffing candy, chips, burgers and French fries down his pie-hole in a futile effort to satisfy his insatiable craving for a constant supply of readily available energy. This guy will be so heavy that seesawing is absolutely impossible. The rhythmicity of the game, is yet not the only thing that is disrupted, the natural and vital rythm of anabolic and catabolic or I should say production and recycling of your opponent is broken, as well.

With the constant abundance of readily available energy and, consequently, a low AMP:ATP (~used to usable energy source) ratio, the AMPK-related phosphorylation TSC2 and RAPTOR (cf. figure 5), which in turn would inhibit mTOR activity is absent. Now, what sounds as if it was taken right from a body builders well-spray-tanned dreams, is in fact as unhealthy as it is unnatural. Not only does it block all the beneficial effects of AMPK, i.e.
  • increased glucose uptake in liver and muscle,
  • increased fatty acid oxidation
  • reduced glucose and fatty acid synthesis, and
  • autophagy
the presence of which in figure 1 you may not even have noticed, when you heard the dreaded word "catabolic". Of these, the latter, i.e. autophagy, may have the least cosmetic value (and some of you may even not know what exactly it is) is of paramount importance for your health - after all, these cellular degradation processes allow your body to constantly rebuild itself, to sort out degenerate cells and make good use (recycle) what would otherwise pile up in form of messy metabolic junk or - even worse - uncontrollably proliferating tissue, i.e. cancer!

AMPK vs. mTOR in energy regulation, health and disease

The seesaw analogy should have made it quite clear that not mTOR or AMPK, but mTOR and AMPK and their interplay constitute the fundamental backbone of an energy sensing and growth regulating system, we have inherited from our earliest, eukaryote ancestors. And with many (if not all) of the major health problems of the Western society being related to a profound disturbance in energy regulation, it is by no means surprising that the chronic (over-)expression of the mTOR pathway (as exemplified by our overweight seesawer from image 1) that is so characteristic of our world of nutritional abundance has recently been implicated in all sorts of...
[...] disease states, where growth is deregulated and homeostasis is compromised, namely cancer, metabolic diseases and ageing (Zoncu. 2010).
Assuming that you have read all previous installments of this series, this should make you sit up: Cancer, metabolic disease (obesity, diabetes, hyperlipidemia,...), even aging (cf. figure 3)... in the past Intermittent Thoughts you have not only read about all of these, but you have also seen that intermittent fasting, in the form of either alternate-day-fasting, or Ramadan fasting was able to ameliorate or even partly reverse all these ailments of an obesity-stricken society, which is about to drown in fructose-corn-syrup and partially hydrogenated vegetable oils.
Figure 3: The contribution of a chronic overactivation of the mTOR pathway on aging
(based on a review of the literature by Zoncu. 2010)
The fast (regardless of whether its background is a religious one or not) breaks the vicious cycle of chronic mTOR (over-)expression and allows the body to start necessary and beneficial catabolic breakdown processes to rebuild, repair and recycle what got damaged and patched together raggedly in the course of the "anabolic" phase. Now, just as even someone with the repair-skills of Bob the Builder ("I can fix it!"), would obviously - at some point - be unable to make up for the wear and tear the furnishings in his house are exposed to, the well oiled cellular repair-machinery of our bodies will also hit a wall, when all the debris is cleared and the excess energy that had been stored away in times of nutritional abundance is either running short or cannot be accessed fast enough to satisfy acute energy demands (specifically of the brain). Yet, while the latter would obviously be much more likely, when after the "magical" ~16h, after which the glucose stores in our livers begin to dwindle (cf. Intermittent Thoughts - Myth 2), the undesirable result of the energy shortage, i.e. catabolism, would always be the same.
Image 2: Do you too have a question related to AMPK, mTOR or Intermittent Fasting, in general? Don't be shy and send it in! Questions, comments and suggestions for future installments of this series can be posted either at the Suppversity Facebook wall, via Twitter or right in the comment-area at the bottom of this page.
Does mTOR make you fat? It may be of interest to some of you (I know someone asked, but forgot who - shame on me) what the effect of the "anabolic" mTOR pathway on adipose, i.e. fat, tissue is. Well, if you look at the obese seesawer in image 1, the question appears unnecessary... if we delve a little deeper into the complicated interactions that are taking place here, we will yet notice that it ain't the mTOR signal per se that is fattening, but the way it sets the stage for increased adiposity by inhibiting the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) (Chakrabarti. 2010), so that stored triglycerides cannot be broken down and released into the blood stream to be subsequently burned as fuel, and, at the same time, by ramping up lipogenesis and thus increasing the lipid accumulation in white adipose tissue (and, in severe overfeeding scenarios, liver and muscle, as well). Without the presence of a chronical overabundance of energy and the consequent over-expression of mTOR in the presence of readily available substrates for fatty acid synthethase, fat storage would however not be a concern. Moreover, if the AMPK-mTOR cycle is intact, the excess energy that is not used for protein synthesis, but stored during the anabolic phase, will come handy to fuel the repair processes when (during a "fast") AMPK takes the reign.
A chronic overexpression of AMPK and consequent catabolism of metablically active tissue (muscle and organ tissue) is unquestionable as undesirable as the fattening, cancer-promoting and life-shortening effects of chronic activation of the mammalian target of rapamycin (mTOR).
Figure 4: Merely illustrative sketch of the interplay of mTOR and AMPK as a function of time [in h] with feeding / fasting periods at the indicated time points.
The sketchy graphical illustration (it should be obvious that neither the sinosodial nor the linear parts are based on actual observational data) of the interplay of AMPK and mTOR and their relation to feeding, and thus energy availability in figure 4 goes provides some clues about how the large fasting window, allows enough time for an acute, yet temporary energy shortage to occur in the course of the postprandial /-absorptive phase, where the constant influx of nutrients which keeps the anabolic mTOR pathway humming runs out and AMPK eventually takes charge, as its activation consequent to the rise in AMP:ATP ratio (=energy shortage) subsequently decativates the mTOR pathway via phosphorylation of tuberous sclerosis protein 1+2 (TSC1+TSC2, cf. figure 5) and their inhibiting effect on GTP-binding protein Rheb, which is the central governor in the regulation of growth and cell cycle progression.
Figure 5: Graphical illustration of the way growth factors, substrate availabilty (amino acids) and energy supply / shortage regulate cell growth and metabolism
The re-constructive yet eventually catabolic reign of AMPK, on the other hand, comes to an abrupt end, as soon as a nutrient-rich meal is ingested and the AMP:ATP ratio rises. This process will obviously not be as linear as I sketched it in figure 4, but it does stand to reason that the length of the transitional period will be somewhat proportional to the speed at which the intracellular ATP levels are repleted. That being said, a tried and proven way to quickly replenish ATP stores is the ingestion of a relatively large bolus of high glycemic carbs.

Carbing up immediately post workout could help you to make the most of the feeding window

Against that background, even low-carbers may suddenly see some sense in adding a reasonable amount of simple sugar to their post-workout shake, especially if they position their feeding-window right after their training session at the gym (which would then obviously have been performed in the (semi-)fasted state). The fast acting carbohydrate would then not only replete the muscle glycogen stores, they would also allow the amino acids that come with both the post workout shake, as well as the subsequent whole-foods meal(s), and the training and nutritionally induced growth factors to do their anabolic magic by releasing the "catabolic AMPK-break" as fast as possible.
Image 3: To "carb up" after exercise simple dextrose is probably enough. It does not have to be the expensive Vitargo. And certainly not WaxyMaize, which has a profoundly reduced 4-hour glucose and insulin responses compared to maltodextrine / sucrose (Sands. 2009)
Carbohydrate timing: Did you know that a 1988 study by Ivy et al. found that there is a statistically highly significant difference in the rate of muscle glycogen storage depending on when you ingest the carbohydrates? In fact, the rate of glycogen storage was 45% slower if the carbs were ingested 2h after exercise (vs. immediately post) and the amount of glucose that was stored in the vastus lateralis muscle of the 12 healthy subjects after 70 minutes on a cycle ergometer at 65% of their individual VO2Max with two intermittent intervals at 88% of their VO2Max was ~25% greater, when the 2g/kg carbohydrate were consumed immediately post-workout. Overall, clear-cut evidence of the repartitioning effect of exercise that would support the well-known advice to "time your carbs around [for someone on an intermittent fast obviously after] workouts".
Now that we are finally approaching the enjoyable part of intermittent fasting, i.e. the feast after the fast, I got the strange feeling that it is time for me to break my own fast, since the increasingly low glucose levels in my liver appear to impact my ability to hear myself think and thus begin to compromise the quality of the Intermittent Thoughts I am committing to the blogger interface.

I would yet assume that you have ingested more than enough information on funky acronyms and modeled signaling pathways to stimulate the neuro-anabolic lEARNing pathway in your brain, so that the intellectual stimulus would ward off any non-beneficial catabolic effects of acute Intermittent Thought deprivation until the next installment will be available - this, I hope, will happen earlier than you may expect ;-)


  1. This series is both informative and enjoyable - thanks doc! :)

  2. Would exo insulin affect insulin post-workout similar to carbing up immediately postworkout?

  3. Also, would the need to carb up post workout to effect the signaling of AMPK be needed if we were not going into the workout glycogen depleted (assuming we refilled the night before and then fasted up until training)?

  4. @Rudolf: thanks for the kind words, Rudolf. These comments really pay for all the work ;-)

    @Future: Sorry for the delayed response - life came in my way *lol*

    exo-insulin would probably have you go hyperglycemic which is 100% detrimental both in view of fat loss, as well as building muscle... so no insulin injections without carbs in a healthy individual.

    in essence, I think the carb refeed is not necessary at all (if you follow DiPasquale's train of thought, which I think is yet pretty controversial) it would even "stop the nutrient influx into the muscle", but then carbs post-workout would hinder muscle gains and the exact opposite (if combined with proteins / aminos) has been shown time and again... it is also not sufficient, but complementary (not via mTOR and insulin, as you may think, though!), to use leucine, but I will break the news on that one in the upcoming installment.

  5. @Future: I forgot to mention - check out these to articles of mine



    on how "unnecessary" yet facilitative muscle glycogen is

    on a side note: I assume that most of us will workout hard enough to deplete glycogen stores anyway

  6. So taking Hmb (supposed mTor activation)during the fast should be negative in this view? (my thought was to keep mTor active, autophaging aminoacids losses, during AMPK activation due to fast and other promoters such as R-ala)

  7. @Bomb Jack: I have / and will address that in the follow up episodes on AMPK, generally speaking, this study > would suggest that you are right, as long as you are just sitting on your ass... before workouts this could yet be very different.

    more on that in

    and follow up(s)

  8. Thank you, Prof.

    Then, your advice is to not to take HMB during the fast unless it's before training (I supposed that before training would be different)?
    Even if I take AMPK stimulators (naringin, R-ala, berberine, resveratrol, etc...)?

    (By the way: your series about IF is great, very interesting & instructional.)

  9. Wow! Just re-reading this series. So great. It seems to me as a non-scientist that we need to honor the natural and healthy see-saw of all hormones and enzymes. Leptin/ghrelin, insulin/glucagon, melatonin/serotonin etc. Chronically elevated or suppressed human chemicals seems to lead to problems. I tried to outsmart my body by eliminating all carbs for years. That did not end well.

    1. glad you like what you read, Meredith. And I must agree, the cyclicity of live - from the smallest to the largest scale - is totally overlooked. Interestingly enough, quantum physics describe the world in cyclic terms, or I should say as a superposition of waves (respectively wave functions)

  10. so,

    doesnt being so long in a lowered mTOR state stunt muscle growth ?

    and doesnt it promote greater catablism due to the AMPK being active for so long?

    thanks in advance

    1. not necessarily, no. Is it possible that the scale will indicate more if you don't fast? YES! Is it likely hat you will lose muscle? BY NO MEANS! Which strategy will have you look better and be healthier? Have AMPK get its right (at least the whole night 8+ hours long)

    2. So what is the minimum time needed to receive a benefit from AMPK? Since a fast doesn't truly start until your previous meal has been digested and absorbed (which typically takes about 5 hours), I feel as though the remaining 3 hours during sleep wouldn't be enough. Even if you eat your last meal 2 hours before bed, how great a benefit is 5 hours of true fasting?

    3. I would say that you need at least 3h after a meal before you even go into a "half-fasted mode" than you will see increases in beneficial effects up to the 14h range, then probably a plateau and then things start getting hairy when you fast over 18h... on the other hand some exercise will do wonders to get your daily AMPK expression in (and that without compromising muscle gains)

      eg. "We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion." -

      There was also a recent study showing that even 8h without food (i.e. practically just the don't eat RIGHT before bed advice had some beneficial effects) AFAIK

    4. Thanks for the response Prof. This was literally exactly what I needed to hear to change up my diet. Trying to fit 3000 Calories into 3 meals + post-workout shake into 8 hours on LeanGains was becoming annoying. However, I still want to reap the benefits of AMPK AND mTOR. If I were to schedule my feedings (see below) like this then would I get ample AMPK & mTOR expression?

      10g BCAA - 6:30am
      Post-workout shake (30g protein) - 8am
      Meal 1 (50g protein) - 10am**
      Meal 2 (50g protein) - 2pm
      Meal 3 (50g protein) - 6-7pm
      **How soon after my post-workout shake should I eat a whole foods meal?

      Thank you so much Dr. Andro. Your advice and reasoning is always interesting and appreciated.

    5. If that's not a casein shake I would say that 40min should be enough to have it so far down in your digestive tract that the "real" food won't hinder its fast aassembly. On the other hand you could even make an argument for less time in-between if you wanted to deliberately slow down the absorption and thus cut back on the insolinogenic effects (see also

    6. Then would it make sense to have my bananas and whey immediately post workout, but then have just protein and veggies (with a little fat) in my first meal ~1 hour after the PWO shake? Since whey is so insulin friendly this would allow for continued protein synthesis but not risk overloading my glycogen and allow insulin to calm down a bit.

    7. the glycogen overload, of which I gather you mean fat deposition is promoted / mediated by insulin, but in the end mostly a result of eating too much. And what's often overlooked (though your suggestion would solve the problem) is that first spiking insulin with whey and then avoiding carbs is the most stupid thing you can do, because a) much of the whey will be used for gluconeogenesis and b) usually this strategy implies having loads of fat instead of the carbs which is easily stored, when insulin prevents its oxidation and promotes its deposition; so in essence that would be a good strategy, but I don't see why you cannot have a handful of rice or other "safe starches" *rofl* with your 2nd meal

    8. I suppose that's good news for a low-carb person, and makes me wonder if that's what Duong did. But anyways, I do enjoy my "safe starches" =)

  11. So how do you think multiple workouts a day affect the see saw? Specifically if strength training precedes conditioning/sport training?

    If one had 2 or 3 sessions in a day, 1 or 2 being conditioning focused, the other heavy strength training, how would that affect the see saw when tinkering with feasting time? Especially working out post feast?

    With high volume training, I wonder if a typical 16/8 window would need to be modified with luecine, or a protein shake, to prevent muscle loss? (Not that it's a major concern) or do you think mtor is even more important with high volume training to help combat the catabolic processes?

    1. you could probably argue that each of the workouts will set you into the "fasting AMPK mode", the only problem is that your CNS is not going to like you to workout all day and all the benefits are probably lost because you end up overtrained in no time (unless you stick to e.g. AM 10min HIIT, launch 30min strength and later afternoon 30min liss or so)

      with high volume training you just eat more after the workout

    2. I'm actually on the national team for judo, and our training loads are very high, as you saw in the Korean judo team study you broke down, which was fantastic. I've done a lot of carb back loading, and have helped a lot of fellow athletes with weight management with it. Experimenting with IF protocols now and seeing great results. Was just curious picking your brain on the nutrient timings and pathway see saws. So assuming one could handle the workload, what do you think is the best way when considering all of the above?