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Exercise And Its Signaling

It’s a truism among metabolic researchers that if you could find a drug that simulates the effects of exercise you would be very happy with the market for it. But what causes the effects of exercise? That’s one of those simple questions that members of the general public might think that they know the answer to already – until you ask for details. Then they might figure that even if they don’t know, that someone in the field does. But do we?  “Exercise makes you use calories” – that’s probably a good thing, but why is it, exactly? Which calories, from where? Exercise makes your muscle tissue take up more circulating glucose – but how is that process started? What’s the actual signal to your cells to (say) mobilize those fat stores that you’re trying to burn off? How do your muscle cells realize that they’re being exercised, and how to they get word to the adipocytes that are storing the fat? How long do these effects last – is it just while you’re exercising, or are there other metabolic effects that linger for hours or longer? It appears that exercise affects many of the symptoms of aging, for example. What are those mechanisms like as opposed to the acute ones? And so on.

We know a bit. Some of the intracellular signals of exercise seem to be the reactive oxygen species that are generated under metabolic stress. There is evidence that taking antioxidant supplements actually negates the beneficial cellular effects of working out, and I have waited, in vain and for years, for word of this to penetrate the nutritional supplement markets. Debate over whether athletes can benefit from antioxidants under particularly stressful hypoxic conditions continues, but I think it’s clear that for regular exercise levels there’s no benefit (and possibly some harm).

What about intercellular signals? This new paper sheds some light, showing that IL-6 is responsible for the signaling that lowers visceral fat stores in response to exercise.These are data from human studies, made possible by the fact that an antibody against the IL-6 receptor (tocilizumab) is an FDA-approved drug for arthritis. Epinephrine has been suggested as the signaling molecule for this, but it appears that IL-6 is more important. It’s mainly the visceral fat that’s affected by this route, though – patients taking the antibody showed no change in that fat depot (as opposed to those who weren’t on the drug), but their total body weight changes and lean body mass values were similar. Different fat stores, in other words, respond through different pathways (an effect that has already been noted in other studies over the years). Food intake didn’t differ between the two groups, but the patient groups taking the antibody actually seemed to spend a bit more time exercising.

Interestingly, though, IL-6 is not involved in cardiac and respiratory fitness improvements – just the mobilization of visceral fat. In line with observations from the clinic, the patients taking the antibody also showed increases in cholesterol. Complicating the picture is the fact that IL-6 may well be acting differently in healthy patients versus those showing “metabolic syndrome” (obesity with cardiovascular and metabolic disturbances, etc). Exercise induces higher IL-6 levels, for example, but so does chronic obesity, probably through a completely different mechanism. And the chronically obese physiology is not doing much about clearing out visceral fat, so something different is going on.

But it does seem clear that under baseline conditions IL-6 is the signaling pathway for visceral fat usage. So what does this mean for patients who are taking the drug? Well, if they’re trying to lose weight, there’s one region of the body that they’re not going to lose it from, apparently.In the antibody-treatment patients who did not exercise, their visceral fat mass actually increased, which can’t be helpful. It’s good that cardiac fitness isn’t affected, and who knows – if that observation about exercise time is real, then it might actually help people to work out a bit more if they’re motivated to do so to start with, of course. But another exercise benefit might be negated – there was a small reduction in insulin levels in the exercise+placebo group, with unchanged glucose levels, which argues for an increase in insulin sensitivity (a known exercise effect). Insulin and glucose levels did not change in the antibody groups, though, so although no harm was done, they may have missed out on a chance to improve their insulin response. And finally, as mentioned, the increase in cholesterol levels with tocilizumab was already known.  Something to consider!

 

10 comments on “Exercise And Its Signaling”

  1. Bryan says:

    The endocannabinoid system is responsible for many beneficial effects of exercise.

    Ok, now that I’ve got your attention, this is at least what I’d like to think. Concentrations of anandamide and 2-AG increase after robust exercise and a recent study pretty convincingly showed them as the molecules responsible for “runner’s high” and not endorphins (PNAS, 2015: https://www.pnas.org/content/112/42/13105)

    This paper has served as my inspiration to get to the gym regularly – thinking I have some control over positive feelings of exercise by temporary release of anandamide? Awesome! Even if it’s partial placebo effect – whatever!

    There are so many complex biochemical and physiological events occurring during and after exercise that I worry one small molecule (or many) is going to fall short recapitulating all of the benefits of exercise. But if we could successfully target one that is fruitful and makes this a very intriguing study.

  2. Lane.Simonian says:

    The advantage of exercise whether via IL-6 or not is likely through the stimulation of the phosphatidylinositol-3 kinase/Akt pathway.

    https://www.ncbi.nlm.nih.gov/pubmed/22705768

    When this pathway is inhibited (as is the case in various diseases) some of the benefits of exercise may disappear.

    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007901

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946113/

    1. AGMMGA says:

      My PubPeer browser plugin automatically flagged the PlosOne paper you linked for image irregularities. A cursory inspection of the online version of the paper shows that indeed, some lanes in figure 3A have been badly spliced together. I don’t have time to read the paper and evaluate how this might have influenced the core message, but caveat emptor…

    1. Lane Simonian says:

      As may show up in a subsequent comment, the health benefits of exercise are largely the result of the activation of the phosphatidylinositol 3-kinase/Akt. Many disease are likely due to the overactivation or inhibition of this pathway–with gingivatis being just one of many factors that fit into this latter category.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335252/

    2. Lane Simonian says:

      Gingipains act in part through protease activated receptors (a family of g protein-coupled receptors) and this is part may explain their potential link to neurodegeneration.

      http://www.jimmunol.org/content/175/9/6076

      https://www.sciencedirect.com/science/article/pii/S1089860309001281

  3. John Adams says:

    Simply put, a very large number of the physiological benefits of exercise are a direct result of AMPK activation (not only in muscle, but other tissues including the liver, adipose and heart). Many of these effects have been replicated by new, systemic direct pharmacological activators of AMPK.

    1. Dan says:

      Or old ones, like metformin

  4. Cishumanist says:

    Just a heads-up that the article on the many benefits of exercise in ageing was published in Aubrey de Grey’s journal “Rejuvenation Research”. Not that I want to criticise an article by its place of publication, but there are better venues for authors and readers alike.

  5. Lane Simonian says:

    To piece a few items together.

    “Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling.”

    “Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes.”

    “Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models”

    “High Glucose-Mediated Tyrosine Nitration of PI3-Kinase: A Molecular Switch of Survival and Apoptosis in Endothelial Cells”

    “Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus” (whatever the limitations of one of the images).

    “Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial.”

    CONCLUSION:
    A moderate to high intensity aerobic and strength exercise training programme does not slow cognitive impairment in people with mild to moderate dementia. The exercise training programme improved physical fitness, but there were no noticeable improvements in other clinical outcomes.

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