Bodybuilding.com Information Motivation Supplementation
in:

AMPk: Master Metabolic Regulator.

The molecule I want to talk about is called AMP-activated protein kinase or AMPk for short, a compound that is turning out to be one of the major metabolic regulators in the liver, skeletal muscle, fatty acids, and the brain.

By: Lyle McDonald

So one way or another I let myself get talked into writing another article. And, having scant else to write about, I suggested a piece on this little bit of molecular biology called AMPk that happens to interest me at the moment.

Ok, great, I imagine there are three or four whole people who care and, as I'm sitting down to write this, I realize that it's going to really be just one long theoretical wank without a lot of application.

At worst, it will bore you to tears. At best, it will help explain some of the issues that go along with both dieting/fat loss and gaining muscle, along with a lot of the underlying physiology of my Ultimate Diet 2.0. I guess that's something anyhow.

The molecule I want to talk about is called AMP-activated protein kinase or AMPk for short, a compound that is turning out to be one of the major metabolic regulators in the liver, skeletal muscle, fatty acids, and the brain.

This is especially true if you're talking about the regulation of glucose uptake and utilization, fatty acid intake and oxidation, and appetite. Ok, maybe I have your attention again.


What Is AMPk And How Is It Regulated1

I'm not going to bore you with a detail of the structure of AMPk. Sufficed to say that it's a heterotrimeric compound (translation to nonscientist: contains 3 different parts which are different from each other) which are all regulated differently.

Sparing you unnecessary details, AMPk is turned on when the cellular energy state of the cell drops. Basically, anything that causes the cell to use energy (ATP is broken down to produce energy and ADP, and the ATP/ADP ratio is a key activator of AMPk) will activate AMPk.

Bioenergetics And Energy Release!
In order to perform work, we need energy. The energy we use to perform actions, such as a sprint, etc. is acquired from the transfer of chemical energy. Learn more below about how energy in the body is processed and created.
[ Click here to learn more. ]

As well, specifically in muscle, levels of glycogen may also regulate AMPk: it appears that high levels of glycogen inactivate AMPk and lowered levels of glycogen activate it.

Activation By Cellular Stress

    Ok, let's get more specific. A number of cellular stresses can activate AMPk. This includes:

    • metabolic poisons (DNP anybody?)
    • glucose deprivation
    • ischemia (decreased blood flow)
    • hypoxia (insufficient oxygen)
    • oxidative stress
    • hyperosmotic stress.

    With the possible exception of DNP use, none of these are going to occur in healthy athletes. A chemical activator of AMPk called AICAR (NOT to be confused with acetyl-l carnitine or ALCAR) is being used in research as a chronic activator of AMPk.

    I thought I had heard rumors that someone was going to try to bring it to market as a fat loss product. As I'm going to explain below, for athletes/bodybuilders, use of such a compound would be a tremendously bad idea.

Activation By Muscular Contractions

    So what else? Well, I already mentioned that glycogen depletion may play a role (this is probably part of why glycogen depletion increases whole body fat utilization). Probably the most relevant activator of AMPk is exercise and muscular contraction, both of which shift both the ATP/ADP ratio as well as the creatine/phosphocreatine ratio.

    I should mention that exercise also activates AMPk in liver and fat cells and this appears to result from exercise induced release of certain molecules such as interleukin-6 (released from muscle cells during intense activity, especially when glycogen is depleted).

    Also, systemic changes in fuel availability during exercise are involved in the activation of AMPk in tissues like liver and fat cells.

Hormonal Control

    AMPk is also controlled by a variety of hormones. Leptin and adiponectin, released primarily from fat cells in response to nutrient surplus, both activate AMPk in peripheral tissues.

    Leptin also appears to decrease AMPk levels in the brain (I'll come back to this paradox below) while ghrelin (released from the stomach in response to eating less) increases levels of AMPk in the brain.


What Does AMPk Do?

Although it's likely that AMPk is involved in cellular control in most cells of the body, I'm going to focus primarily on liver, skeletal muscle fat cells, and the brain (specifically the hypothalamus, which is the area primarily involved in appetite/hunger and bodyweight regulation) with AMPk playing a role in carb, fat and protein metabolism in peripheral tissues and bodyweight regulation in the brain.

Carbohydrate Metabolism

    With regards to carbs, AMPk activation inhibits glycogen storage and increases glucose uptake, it appears to be very involved in improving insulin sensitivity for this reason.

    Insulin sensitizing drugs such as metformin and the thiazolidinediones (TZD's) appear to work at least partially through AMPk activation. Note that the TZD's tend to increase body fat and metformin hasn't been found to cause a drastic decrease in fat mass by itself either2 although it seems to improve the results of low-carbohydrate diets in insulin resistant/obese individuals.

Fat Metabolism

So what about fat metabolism? In the liver, AMPk activation decreases fatty acid and cholesterol synthesis. In muscle cells, AMPk activation increases fatty acid oxidation (i.e. you burn more fat).

It also appears that AMPk activation is one of the keys to how endurance training causes adaptations such as increased mitochondrial protein synthesis3. In fat cells, AMPk activation decreases both fatty acid synthesis and lipolysis (by inhibiting hormone sensitive lipase).

Fat Metabolism!
Dietary fat is not an enemy. In fact, when adequate amounts of good fats (unsaturated) are consumed, it can improve one's health and athletic performance. Learn what these good fats are and how they keep the body function properly.
[ Click here to learn more. ]

Protein Metabolism

    Ok, so far so good, right? With the exception of the inhibition of lipolysis, it sounds like AMPk activation is a good thing, increased glucose uptake, increased fatty acid oxidation in skeletal muscle cells. So why not just jack up AMPk levels all the time and get ripped?

    Reason One

      The first reason I alluded to in the UD2.0, a low cellular energy state inhibits protein synthesis. And it looks like AMPk activation is part of the mechanism. In a rat model, AMPk activation has been shown to suppress protein synthesis by down regulating another molecular target called the mammalian target of rapomyacin, or mTOR4 which is heavily involved in protein synthesis.

      Although this hasn't been shown in humans to my knowledge, the general picture is that AMPk activation turns off energetically costly processes (such as protein synthesis) and turns on energy producing processes (such as glucose and fat oxidation).

      So an AMPk inhibition of skeletal muscle protein synthesis would be consistent in humans. I'll note that years ago, Dan Duchaine commented how insulin sensitizers (of which metformin was one of the ones in use) caused muscle loss and I have to wonder if this isn't part of the mechanism.

    Reason Two

      The second reason has to do with the effects of AMPk activation in the brain where AMPk activation has a rather negative effect, which is to increase appetite. Recall from above that I mentioned that both leptin and ghrelin affect AMPk levels in the brain. Well, it's time to talk about that.

      As mentioned, ghrelin, which tends to increase appetite and food intake increases AMPk levels in the brain while leptin, which tends to decrease appetite and food intake (sort-of) decreases AMPk.

      As well, nutrient availability affects brain AMPk (probably through leptin and ghrelin). Eat more and brain AMPk goes down, eat less and brain AMPk goes up5.

      Increased activity of hypothalamic AMPk via AICAR also increases food intake6. I'll come back to the ramifications of all of this below. I want to mention that the mechanism whereby leptin increases AMPk levels in muscle but decreases them in brain is currently unknown7

      That is, leptin has opposite effects on AMPk in muscle/fat/liver cells versus the brain.


Putting It All Together

So now a few things may start to come together in terms of dieting or mass gains or what have you. When you eat less (diet), a lot of things occur.

  • One of those is going to be a decreased cellular energy charge (an effect which may be increased by glycogen depletion and, of course, exercise).

  • Fat oxidation goes up; insulin sensitivity goes up, good things happen in terms of fat loss.

  • But the drawback is that, due to changes in hormone levels and AMPk signaling you get hungry.

  • As well, protein synthesis is inhibited (this is a huge part of why it's so hard to gain muscle while losing fat at the same time).

AMPk and its function also explain one of the older models of hypertrophy whereby protein synthesis was acutely depressed during exercise. Activation of AMPk during exercise directly inhibits mTOR and protein synthesis. The recovery of cellular energy post-workout allows protein synthesis to increase and growth to occur. Note also the huge push on the provision of amino acids, specifically leucine, post-workout as leucine directly activates mTOR, turning on protein synthesis.

Override AMPk?

    A question that comes to mind (which I have no answer to): can leucine's activation of mTOR override the AMPk suppression of mTOR either during exercise or while dieting? High dose BCAA may decrease muscle loss on a diet, could this be a potential mechanism?

    In reverse, consider what happens when you're eating above maintenance. AMPk will be inhibited (except during exercise) meaning no inhibition of protein synthesis. Also, assuming decent brain leptin sensitivity, appetite and food intake will be kept under control. However, this comes at the expense of decreased fat oxidation (part of why folks tend to gain fat as they gain muscle).

Can't Have Your Cake And Eat It Too

    Basically, AMPk (and, make no mistake, there are multiple other pathways involved) help to explain why it's so hard to have it all: fat loss with muscle gain. As described in the UD2.0, the mechanisms needed to maximize fat loss are more or less directly antagonistic to those mechanisms involved in muscle gain and vice versa. This is why the UD2.0 was broken up into discrete fat loss and muscle gain phases which were alternated every few days. A few words about application

    As mentioned in the introduction, this article didn't really present a whole lot useful, I'm wondering why I'm wasting your time with it. Clearly, the most potent tool we have to activate AMPk and increase fat oxidation and the rest is exercise. Dieting in general probably activates AMPk as well although I can't recall seeing it directly studied.

    The effects of both can be increased by depleting glycogen (ala the UD2) but this comes with the price of inhibited protein synthesis. This is why I'm so adamant about all diets having a refeed/anabolic phase at some point. You need to turn off diet induced catabolism although I should note that AMPk activation is only one of many mechanisms (including insulin, cortisol, etc, etc.)

    Under non-dieting circumstances, although AMPk will be activated during training, impairing protein synthesis, providing nutrients afterwards (i.e. carbs + proteins) is known to reverse the catabolic processes and turn on anabolic processes. Making me wonder if pre- or during-workout nutrition can actually prevent the activation of AMPk in the first place (by limiting the drop in cellular energy charge). To my knowledge, it hasn't been studied but it would make some logical sense.


A Final Question About AMPk & Fat Loss

From the standpoint of treating obesity and insulin resistance, AMPk appears to be an attractive target. However, the contradiction described above has to be dealt with. Ideally you'd want to activate AMPk in peripheral tissues such as muscle and fat cells while decreasing AMPk in the brain (to reduce or control food intake).

Clearly leptin injections are one way of doing that but leptin injections are unlikely to work in obese individuals, due to leptin resistance, in the first place. Of course, lean athletes and bodybuilders aren't obese and probably have decent leptin sensitivity.

This is probably one of the reasons refeeds 'work'. By raising leptin, we are activating AMPk in skeletal muscle (explaining why people often lean out after a refeed) and inhibiting it in the brain. Is there any other way? Well, maybe.

One study (again, in rats) found that alpha-lipoic acid ingestion decreased AMPk in the brain while increasing it in skeletal muscle in rats8. I should note that the doses used were high and a very informal poll on my forum doesn't seem to indicate that ALA was having any such effect in terms of fat loss or appetite. If anything, people noted an increase in appetite, most likely mediated by a decrease in blood glucose via insulin sensitization. Would consuming ALA while eating sufficient carbs allow us to achieve the same effects without increasing hunger? I don't know. There is also the dose issue.

But it does point out that increasing AMPk in muscle while decreasing it in the brain is possible and future drugs or nutrient compounds may allow us to get the best of both worlds. Unfortunately, there is still the issue of muscle loss due to the inhibition of protein synthesis that would occur with chronic muscular activation of AMPk. At this point, I have no idea how to sidestep that. Would sufficient amounts of protein, BCAA or even just leucine be sufficient to activate mTOR against the inhibition occurring due to AMPk? Or would another drug or nutrient be required to prevent muscle loss against chronic AMPk activation. At this point, it's all speculation; hopefully more research will help to answer these questions.

Author Bio

Lyle McDonald is a physiology geek and general pain in the ass who is really bad at coming up with article ideas. He is the author of The Ketogenic Diet, Bromocriptine, and The Ultimate Diet 2.0 and has two new books just released: The Rapid Fat Loss Handbook: A Scientific Approach to Crash Dieting and A Guide to Flexible Dieting. The first new book details a modified protein sparing modified fast for rapid fat loss, the second deals with such concepts as free meals, refeeds, and full diet breaks to help with long-term dieting. All of which can be ordered through his website.

References:

  1. Kahn, BB. et. al. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism (2005) 1: 15-25.
  2. Ruderman NB et. al. Minireview: Malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology (2003) 144: 5166-5171.
  3. Aschenback, WG et. al. 5' Adenosine monophosphate-activated protein kinase, metabolism and exercise. Sports Med (2004) 91-103.
  4. Bolster, DR. AMP-activated protein kinase supresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapomyacin (mTOR) signaling. J Biol Chem (2002) 277: 23977-23980.
  5. Minokoshi Y et. al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature (2004) 428: 569-574.
  6. Andersson U. et. al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem (2004) 279: 12005-12008.
  7. David Carling. AMP-activated protein kinase: balancing the scales. Biochimie (2005) 87: 87-91.
  8. Kim MS et. al. Anti-obesity effects of alph-lipoic acid mediated by supression of hypothalamic-AMP-activated protein kinase. Nat Med (2004) 10: 727-733.

Lyle McDonald

Visitor Reviews Of This Article!
Read Visitor Reviews - Write Your Own Review

Back To CORE Training's Main Page

Back To The Articles Main Page.

Related Articles
Vindicating Vitamins: Protecting Your Health Is Never A 'Waste'
WHY YOU NEED WHEY
Everything You Need To Know About Greens Supplements



RATE THIS ARTICLE
POOR
  • 1
  • 2
  • 3
  • 4
  • 5
  • 6
  • 7
  • 8
  • 9
  • 10
EXCELLENT
OVERALL RATING
10

Out of 10
Excellent
10 Ratings

0

Comments

Showing 0 - 0 of 0 Comments

(5 characters minimum)

      • notify me when users reply to my comment
Showing 0 - 0 of 0 Comments

Featured Product

Give Us Feedback:
Report A Problem
Site Feedback
Follow Us:
Twitter
Facebook
RSS Feeds
Bodybuilding.com Newsletter

Receive exciting features,
news & special offers from Bodybuilding.com