A Step Toward Health Benefits Of Exercise In A Pill?

We're a long way from being able to bottle the myriad benefits of exercise, but a study just out in the journal Nature looks like a promising step in that direction. It describes the discovery of a naturally occurring hormone christened irisin — pronounced like the name "Iris" with an "in" tacked on the end — that is elevated during exercise in mice and humans.

Irisin appears to be a possible key to the positive effects of exercise on blood glucose and energy expenditure — and thus on Type 2 diabetes and obesity. And because it is naturally occurring, it could be tested in humans fairly soon, perhaps in a couple of years.

But before we get to the science, a word from the study's senior author, Dr. Bruce Spiegelman of Harvard Medical School and the Dana-Farber Cancer Institute. To all the negativity-mongers (my phrase, not his) out there who will grumble (my verb, not his) that this discovery will just enable more slothfulness, and would be unnecessary if all those couch potatoes would just get off their butts and eat better, please consider:

"The last thing in the world we're trying to do is substitute for diet and exercise," Dr. Spiegelman said. But first of all, there are many people who can't exercise, whether because of paralysis or age or illness, he said. Work on irisin could potentially help them.

Second, yes, everybody should exercise and eat right but they don't. Obesity and diabetes are worldwide epidemics costing untold billions, he points out. If irisin proves able to help fight them, it could benefit all of us.

Our conversation, lightly edited:

So where did the name irisin come from?

Iris is the Greek messenger goddess who carried messages between humans on earth and the gods on Olympus. We didn't want to name it for any specific function because we don't know what all of those are going to be, and what the most important are going to be, so instead we named it for its messenger function.

So what did you already know, and what did you find out? 

What we knew was that a molecule that we discovered in the late '90s called PGC1-alpha gives muscle many of the attributes of exercise, and we also knew that elevated PGC1-alpha in muscle causes the animals to be relatively resistant to age-related obesity and age-related diabetes. Based on that, we thought there was a chance that PGC1-alpha was not just working within the muscle but actually was causing the muscle to secrete molecules that affected the health of other tissues and organs in the body.

So we set out to identify molecules that are regulated by PGC1-alpha in muscle and that might be secreted proteins, and we identified a small number of them, and tested them for their ability to do the function we were specifically looking at, which is the "browning" of white fat — turning on a thermogenic program in some white fat.

I tend to think of brown fat as good, because it actually burns energy — it's been called 'a fat that helps you lose weight,' and white fat as bad...?

In general you can think of it that way but it is also true that certain white adipose tissues can be stimulated to take on a thermogenic, brown-like character. So there is some transition between the two, especially subcutaneously, and this is exactly what we found the function of irisin to be. If you put it on certain kinds of white fat cells it will encourage them to develop into brown-fat-like cells both in a culture dish and in the organism.

That's what my lab works on: the development and function of adipose tissues and muscle. It’s sort of the sweet spot of my lab. It wasn’t a random thing we happened to look at in fat. We have identified some of the major regulators of adipose tissue over the last 25 years.

So the fact that you've identified irisin — what does it promise?

One of the main things that are specifically exciting here is that irisin is a polypeptide and so conceivably could be made into something that could be injected into humans without too much trouble.

So is this the holy grail of an obesity-fighter?

Ah, one dreams that...
The cool thing here is that this is natural product. It’s really secreted by muscle; it has this function; we know that at least within a certain window among sedentary people and people who exercise there doesn’t seem to be any side effects in vivo. So yes, there's the dream, at least, that this could have powerful effects on metabolic disease and perhaps in other diseases as well, but of course that will have to be proven.

So how would it work if you could do in humans what you did in mice?

We would need to develop an effective form of the protein that has good drug-like properties, meaning it's relatively stable in the blood, and we're working on that now. We have some forms that seem relatively stable in the blood. And then as long as we don’t see any toxicity in animal studies it could theoretically go forward to clinical trials. Because it's a natural product one would like to think it could be developed a little faster.

Exercise is so great for our health in so many ways. How much of that could be accounted for by the action of irisin?

We don’t know. That's a very good question. We do know in mice that this accounts for a substantial amount of the browning of white fat with exercise. We have it in the paper: We exercised mice with an antibody neutralization of irisin, and it really cut down the ability to brown the white fat. So in that specific niche, it looks like a substantial player.

Just to fantasize, say you develop the human version and inject it — what happens?

What we know so far is that it has anti-obesity and anti-diabetes effects in rodents.

How much?

We only carried the studies out for a week or 10 days. That can’t be answered based on what we’ve done so far. The other things is that exercise benefits other systems of the body, and we are anxious and hopeful to apply this first in experimental models to see if it brings about any of the other known benefits of exercise. For example, in diseases like ALS, where patients would benefit from exercise but can’t exercise. So that's a very exciting possibility, to see whether this has benefits over and beyond metabolic disease.

We didn't identify it based on metabolic disease, just as a secreted factor from fat and muscle which is regulated in exercise. So it could embody some of the other benefits of exercise on neuromuscular systems, on the brain, on the heart — we have no idea. It'll be fun to do those studies. To have even some portion of the benefits of exercise embodied in a polypeptide is very exciting.

So if we get an irisin pill, might I be able to become a couch potato but stay healthy??

I specifically want to address this: Nothing can replace diet and exercise. They bring about a lot of benefits. But I also would like to point out that some people can’t exercise, either because they have physical problems, they're bedridden, or because of injury or illness. So there's a need for a medical therapy that can mimic exercise, primarily not to let people avoid exercise but simply to provide benefits to people who can’t do it.

Could irisin possibly be involved in the causes of the obesity epidemic?

What you're asking is: Could it play a role in the causality of obesity and diabetes? Could some people be deficient in it for one reason or another? They could be deficient because they don't exercise; could they be deficient for other reasons? Absolutely — it remains to be seen.

Was the discovery of irisin a surprise or a logical progression?

We discovered PGC1-alpha in 1998. We first discovered its important role in bringing about exercise-like actions in muscle in 2002. We discovered in 2009 with collaborators that mice with PGC1-alpha just in muscle were resistant to age-related diabetes. So after that was published, we began to think that PGC1-alpha might be controlling secreted molecules that were talking to the other tissues.

It was a long-term but relatively logical progression. We didn’t wake up one day and say this, it was ten years of work. It does highlight a crucial point, which is that research is slow and it takes a long time, and you can’t just walk into a lab and in most cases make a breakthrough. This was a number of very, very good fellows working over a 12-year-period for us to come to this point. It was actually a pretty linear but long-term process where we were talking in the lab for a couple of years about what PGC1-alpha was making the muscle secrete, and sure enough we found such a set of molecules.

What next?

We want to know what the receptor is at a basic science level. This is a polypeptide in the blood, presumably fat and other tissues have a receptor. What is it? How does it signal? That’s a big issue. And it opens the door wider for pharmaceutical development.

And we're moving things forward as quickly as we can in the direction of human clinical trials. If everything goes smoothly, that could be within two years. It's a natural product, it's in your blood and mine. We don't know how this is going to turn out, but this is for me perhaps my holy grail — as a PhD scientist finding a polypeptide secreted into the blood that brings about good effects — if it does work, it could go very fast.

The intellectual property has already been licensed to a company called Ember. I was one of its founders though please note that I was recused from the negotiations; it was Dana-Farber Cancer Institute that licensed it to Ember. To develop a product to put in human beings, it has to be done according to pharmaceutical standards and that’s not something my lab does. I'm still involved from a scientific perspective but obviously this gets ways beyond what my academic lab would do.

So how would you put this in perspective? How big a step forward is this?

I think people have been thinking for a long time that exercise has benefits that go well beyond the muscle. It affects your heart, your blood vessels, it’s very anti-diabetic. So to find a polypeptide that embodies some of that is very cool. And we would like to know how it’s regulated, what all its activities are, what receptors it uses, things like that. So it opens up a lot of doors, and whether this makes it clinically or not, we can't know that right now, but I can pretty much guarantee that we will push it as hard as we can.

Other coverage of the Nature paper:
Technology Review
The Boston Globe
The New York Times
New Scientist
Harvard Magazine