What's fuel for the body is fuel for the brain: a story of glycogen

Feb 29 2012 Published by under Behavioral Neuro

It's kind of sad to me how slowly science can move from the laboratory to the classroom (perhaps less critically important than moving from the lab to the bedside, but still pretty critical). I'd like to think with the popularity of the internet and the spread of science communication direct to your screens (hello!), we'll be moving the latest science to the classroom, but when I was but a sprog, things were different. For example, I was raised in high school and college to think that we were born with all the neurons we would ever have. It turns out, all that time, science knew full well that wasn't the case.

And here's another. In college, heck, in grad school, I learned that neurons only eat glucose. Only glucose. Disdain all other molecules. But it turns out, that's not the case either, and we've known for more than a decade! Neurons aren't such picky eaters after all, they'll eat glycogen, the secondary form of energy storage which we usually think of as being used by muscle.

But it gets wilder than that. A reader pointed me to a recent column from Tara Parker Pope, showing that not only does the brain use glycogen as a source of energy during exercise, but that it can "train" to store more glycogen when the body receives exercise training! Being a running addict as I am (and taking a grudging day off right now for the sake of my knees), I wanted to take a look.

And the best part? Rats on treadmills.

(I should note they seem less than enthusiastic. Usually rats really enjoy running in things like wheels. Can't say as I blame them though, I hate treadmills too.)

Matsui et al. "Brain glycogen decreases during prolonged exercise" Journal of Physiology, 2011.
AND
Matsui et al. "Brain glycogen supercompensation following exhaustive exercise"Journal of Physiology, 2012.

Most of us know that during exercise, your muscles use up the readily available glucose (the preferred cellular fuel) in the bloodstream first. Then they move on to stored glycogen, stored to some extent in the muscle and with more stored in the liver. Glycogen can be broken down quickly to lactate and works fairly well as an alternate energy source. When you run out of glycogen stores, you hit physical exhaustion, where you just can't keep going. Athletes call it "hitting the wall" (running out of muscle glycogen) or "bonking" (running out of liver glycogen). Both of these are unpleasant. There are often tears.

Of course, this happens in your skeletal muscle, the muscles doing most of the moving. But what about your brain? It takes a lot of activity in your brain to do something as simple as running, there is a lot of coordinated firing to keep muscle coordination going, keep the legs moving, and any extra conversation with your running partner? Bonus. We used to think of the brain as being a glucose hog. It turns out it still is, but it also will utilize local stores of glycogen, produced by neuronal support cells in the brain known as astrocytes.

What the authors showed in their first paper was that, in the brain as in the muscle, working out to exhaustion will deplete glycogen stores in both places.

What you can see here are glucose (top left) and glycogen measures (all the rest) in either sedentary rats or rats that ran on a treadmill for 120 minutes (TWO HOURS of moderate speed running. I'm impressed). You can see that glycogen stores were well depleted in the muscle and the liver, and also depleted in various areas of the brain, especially the cortex, cerebellum, and hippocampus. It turns out that it has to be exhaustive exercise. 30-60 minutes of treadmill running isn't going to do it.

But that's just one long run, followed immediately after by the measurements. What if you let your rats recover and refuel?

What you can see here are the recovery curves for glycogen stores in the brain, liver, and muscle. You can see that the brain is indeed a greedy organ, recovering glycogen stores more speedily than the muscle or liver. In general, the brain fully recovered glycogen stores, even overcompensating a little, in 6 hours, while muscle followed behind at 24 hours to peak, and liver coming in last at 48 hours.

But what about if you put your rats in "training"? We know that when muscles are trained, they actually increase the amount of glycogen they can store, becoming more resistant to fatigue. What about the brain? The authors put the rats through a three week regimen of 60 min runs, 5 days a week, running about 20 m/min (that's 1.2 kilometers, or a little less than a mile, and considering the size of the rat, a pretty long jog). They then looked at glycogen stores.

While all the trained rats lost weight and fat compared to sedentary rats, they GAINED glycogen stores, in the muscle, and in the brain. The authors hypothesize that this long term overcompensation could be the brain and body's response to the increased energy demands associated with a long term exercise regiment. But the article in the NY Times (and other studies looking at glycogen demands and memory formation) goes further, speculating that this may lead to the increased cognitive function associated with exercise. I feel like we'd need another study to prove that, something that linked exercise with increased basal cognitive function as well as increased use of glycogen stores during that cognitive function, but it's a very interesting idea. In the meantime, think of your brain glycogen stores while you exercise. Your muscles aren't the only thing being trained.

Matsui T, Ishikawa T, Ito H, Okamoto M, Inoue K, Lee MC, Fujikawa T, Ichitani Y, Kawanaka K, & Soya H (2012). Brain glycogen supercompensation following exhaustive exercise. The Journal of physiology, 590 (Pt 3), 607-16 PMID: 22063629

Matsui T, Soya S, Okamoto M, Ichitani Y, Kawanaka K, & Soya H (2011). Brain glycogen decreases during prolonged exercise. The Journal of physiology, 589 (Pt 13), 3383-93 PMID: 21521757

Acknowledgements: This paper comes to be courtesy of Pipettes and Paintbrushes, who sent me a link to the NY Times coverage and asked for my thoughts. Head over there, say hi. :)

19 responses so far

  • Ewan says:

    Hmm. More substantive comment when I get to read the actual papers, but there have been previous reports of brain glycogen supercompensation that turned out to be a methodological artefact - see e.g. Herzog RI, Chan O, Yu S, Dziura J, McNay EC, Sherwin RS. Effect of acute and recurrent hypoglycemia on brain glycogen concentration. Endocrinology (2008) 149(4):1499-1504.

    Thanks for pointing me at the studies!

  • Ewan says:

    Also, of course, (i) neurons need glycogen to be broken down to glucose (more likely, to lactate) before they can use it, so the traditional dogma isn't really thus disproved; but (ii) the whole MCT-vs-glucose issue is a big deal and (iii) it's likely that other sources - even ketones from fat! - can in fact be used if the need is big enough.

    • Scicurious says:

      Oh yes, I presume the glycogen is being broken down to lactate, I just thought that neurons weren't even in to lactate. I heard a lot about how the brain ONLY likes the glucose.

      • A.I. says:

        The brain does prefer glucose, since it's the main energy source that is obtained from the blood. However, there are various research groups supporting the idea that under synaptic activity neurons prefer lactate over glucose, and that this lactate is released by astrocytes. The Astrocyte Neuron Lactate Shuttle (ANLS) hypothesis was first proposed by Luc Pellerin and Pierre J Magistretti ( Review by Pellerin L, Magistretti PJ. (2011) doi:10.1038/jcbfm.2011.149.) As Ewan said the monocarboxylate v/s glucose issue is a big deal, some suggest the opposite theory (neuron to astrocyte NALS), yet still consider lactate in the equation.

        Since neurons don't synthesize glycogen it's probable that astrocytic glycogen is used as a glucose source then converted to lactate and released to feed hungry neurons. And the increase with training (though not as great as after 2h exercise and 6h rest) will probably help sustain brain activity for a (little) while longer. I'm not so interested by this as I am by the differential resistance to depletion.

        The figures show greater depletion in hippocampus, cerebellum and cortex after exhaustive exercise (areas with higher activity during exercise?). And after training glycogen is increased in hippocampus and cortex. I wonder if glycogen metabolism enzymes were upregulated after training (e.g. glycogen synthase or glycogen phosphorylase) to ensure a more rapid glycogen synthesis/degradation. If so, was it only in the areas that suffered greater depletion after 2h or higher increase after training? (I can't access Matsui 2011, but it's not in Matsui 2012)

        Now a little off track, this reminded me of I paper from Cell I read last March that suggests that glycogen utilization (and further lactate release) were required for memory formation. (Susuki 2011, DOI: http://dx.doi.org/10.1016/j.cell.2011.02.018)

        And now way off track. Did you know that while neurons don't synthesize glycogen they do express glycogen synthase? And that activation of glycogen synthase causes abnormal glycogen deposits in neurons and neurodegeneration? This is observed in Lafora disease, a form of epilepsy caused by mutations in malin and laforin genes (Vilchez 2007, doi:10.1038/nn1998 and Valles-Ortega 2011, DOI: 10.1002/emmm.201100174).

        Now I'm off to do some reading. Interesting topic. Thanks for your posts btw. They're always fun to read!

  • m. says:

    Hey, Sci, can you recommend a book (for a layperson) about the chemistry of the body, the metabolic processes and how we store energy, what happens in the brain when we take certain drugs or are exposed to certain stimuli, how painkillers work, etc? I don't know who to ask, I though you might be able to recommend something. I want to learn more about my body, it is an immensely interesting topic about which I know very little :)

  • KateClancy says:

    Sci, this is so useful! I'm going to be talking about nutrition to my roller derby league on Thursday, and one of the things I'm going to cover is that you need to fuel your body and mind appropriately, because muscle endurance AND mental acuity are both important to performance. This really helps me think about and articulate the issue better.

    Also interesting that muscle glycogen repletes in only 24 hours -- I thought that took longer because of the fact that I still feel tired after hard workouts more than 24 hours later. But that must be pain from small muscle tears. It also shows that carb loading can really happen just the day before performance to up your glycogen stores even after a workout. The question is just how fresh you want your muscles to be in terms of a taper.

  • Brandon Poe says:

    As an Anatomy & Physiology teacher, I present the glucose-only fuel issue to my students. I don't feel that this article impacts that. In explaining that the brain only uses glucose, I am stressing the use of carbohydrates. Elsewhere in my course I explain that mitochondria don't have to have glucose to complete ATP synthesis, other carbohydrates can substitute (as can lipids and amino acids). The glucose story is really just to include glycolysis in the set of reactions discussed. The point is, instead, that the central nervous system does not use lipids or amino acids as a fuel source. The importance of that, which I stress explicitly in my course, is that nervous tissue can't give up those macromolecules to the mitochondria since they are necessary for other functions. Imagine the iconic picture of the anorexic with no muscle mass or fat stores. That doesn't happen to the brain because lipids are crucial for cell membranes and myelination of axons while proteins are crucial for neuronal shape (cytoskeleton) and electrochemistry (ion channels, etc.). If those molecules are sacrificed for energy metabolism, then the nervous tissue can't function.

  • Jon F says:

    Back at my old lab working with SOD1-G93A mice on ALS my boss had me doing a bunch of stuff involving neuronal stores of glycogen in specific brain regions to bolster his hypothesis of disease progression based on improper or deficient glycolysis in motor neurons (I would love - love - to be able to link to it since it's mostly my work but he's still sitting on the data, 2 years later. Distractable PI is distractable). We didn't get much into exercise but I do know that 1) non-eccentric exercise - that is, low-impact aerobic exercise - has been shown to extend survival in ALS patients and mice; 2) eccentric exercise - that is, pro-inflammatory and/or anaerobic exercise - has been shown to DECREASE survival in mice and is well-defined as a chronic risk factor for ALS; and 3) we found glycogen to be significantly reduced in areas of CNS most affected by motor neuron death in G93A mice (again, not written into a manuscript yet but I know we threw it into an SfN poster a while back so it's cool for me to mention it).

    All this is a very roundabout way of saying that, based on my personal research experience, I'd say that glycogen use and glycolysis in neurons is probably a lot more delicate and important process than we're entirely giving it credit for. The whole "and then the CNS uses up a crap-ton of energy but it's totes cool, you guys!" thing is probably an area ripe for exploration. Thanks for sharing a paper illustrating that!

  • Emma says:

    Love it - you did such a good job of covering the paper! Happy Monday/

  • Susu says:

    Hi,

    I am not a science guru but most of this made sense to me - I'm curious because I have picked up running recently but I also suffered a major brain injury 1 year ago - and I'm dealing with fatigue - also I diet alot and that means limiting carbs - funny thing is there were times I could run very low on carbs and never "hit the wall" and there are times that I hit the wall after 1o min (i ran 2 half marathons since my accident) so also I'm dealing with "mental fatigue" which turns into physical fatigue where I can't do anything - forget running, just cooking and moving is unbearable. I am trying to figure out is it possible that because its only been 1 year and because I had brain surgery will my brain being in recovery and also having less neurons and cells post injury will I need more or less glycogen or glucose or whatever to keep it fed and behaving to keep me less tired so I can do all the things I need to do, namely run and keep a job (which is very taxing on my brain as I am a business analyst in Technology industry) I found that working my job made me more tired than running half marathon. There are days I cheated on my diet and had pizza (like a whole one -love eating) and next day had the best RUN ever considering I had fatigue for previous 5 weeks - made unbelievable gains in time - shaved 5 min total off 7 k which was horrible to start with) then I went back on diet, literally only allowed 1 toast and 2 fruits a day and next time I ran, 2 days later, I couldn't even do 2 km - I had to stop HAD to at 13 min. So I am confused bc I am eating a lot of veggies and some fruit but is this not enough to run? Also could my brain now that its working twice as hard to live and function (remaining neurons taking on work of lost neurons in accident and surgery) could it be taking up more glycogen esp if I am eating less to lose weight so it leaves not much left for muscles? I'm not a scientist and I am basing this off my personal experience and readings. Also before my injury last year I used to work out with a trainer min 4 times a week and i could run for like 45 min and lift and do interval training another 30 or 45 min and ate same or less than now - so I know there must be something related to my brain injury knowing that brain needs glucose and glycogen to function (only knew that post accident) it seems everything is a struggle now. Whoever can help with comments and with this theory please give any suggestions you can.

    • SO says:

      Susu,

      If you read anything on sports nutrition, you will likely hear the expression, when it comes to endurance sport, that "carbs are king". I can't tell you too much about the brain injury situation, but the bottom line is that low carb diets are not particularly effective for high energy demands of endurance athletes.

      However, regardless of whether you are eating a low carb diet most of the time or not, the most important nutritional strategy to ensure that you don't hit the wall is to fuel with carbs just before and during exercise. We can store approx 60 grams of of carbs as glycogen prior to exercise - and during moderate to intense activity, we will burn that 60grams in about an hour. Just prior to and during exercise (if your total activity is longer than 45-60min) make sure you are consuming 60grams of carb per hour (best at this point are simple sugars as they get into bloodstream most quickly - this contradicts what all diet books say, but fueling for sport performance has different demands than weight loss; the exercise output will flatten the insulin response - you need quick fuel; professional athletes down jelly beans and sugar filled, easily digestible snacks throughout their games and competitions to ensure they keep glycogen stores up).

      Understanding your energy needs overall, however, is far more complex than just looking at carb intake and exercise output. It is an ongoing, delicate balance between stressors (energy out) and recovery factors (energy back in) - of which there are multitudes to identify and comprehend. I recommend that you get in touch with Dr. Sean Richardson - PhD in Sport Psychology - research expert on overtraining, burnout, managing energy and decision making in the elite sport context.

      Good luck!

  • sherry says:

    Compliments to the author for making this article enjoyable to read. I am an athlete and went online to understand why my brain is so under-functioning 1+ hours after a hard workout. Decreased glycogen is my best guess. I laughed a lot after reading this: "Athletes call it "hitting the wall" (running out of muscle glycogen) or "bonking" (running out of liver glycogen). Both of these are unpleasant. There are often tears." So funny! Thanks for that! :)

  • […] Your body can only use a small amount of glucose as fuel. The rest gets stored as glycogen. However, what becomes problematic is that your glycogen stores are also limited – meaning any excess gets stored as fat. You can quickly see why this would become a problem. […]

  • Mike says:

    Very interesting and fun to read. Knew most of it but didn't realize that the brain was capable of carboloading :-)

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