Exercise And Its Signaling

By Derek Lowe 24 January, 2019

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!