How a fat hormone might make us born to run

Last weekend, I ran the Navy-Air Force half-marathon. After pounding pavement for an hour or so, my legs began to feel light. Slightly numb. I felt fantastic. I had to remind myself to run, not to stop and dance, and that singing along to my candy-pop workout music — even at mile 10 — is not socially acceptable. It’s the hope of this euphoria — this runner’s high — that keeps me running.

We’re not totally sure what’s responsible for this incredible high. Some studies call out our body’s endorphins. Others point to cannabinoids — chemicals related to the active compound in marijuana. A new study suggests that the appetite hormone leptin may play a role in getting us going. And from an evolutionary perspective, it makes good sense. When our dinner might make a quick getaway, it’s important to link our drive to run with our need to feed. But it’s probably not the whole story. Like many other neurobiological events, the exact recipe for runner’s high is complex and hazy. It takes a whole suite of chemicals to help us get started and to make sure we want to go the distance.

Those who get runner’s high know it when they feel it. But a clinical definition is a little more slippery. “I remember someone saying the runner’s high was the moment when the body was disconnected from the brain,” says Francis Chaouloff, who studies running and motivation in mice at the French Institute of Health and Medical Research in Bordeaux. This sense of extreme euphoria, he says, is generally limited to people running or exercising for long periods of time, over many miles or hours.

But others have a milder definition. “We use the [phrase] as a way to capture a pretty broad range of psychological changes,” says David Raichlen, a biological anthropologist at the University of Arizona in Tucson. “I look at it at one level as just an improved general feeling of well-being that encompasses mood and…positive neurobiological responses.” This could mean euphoria from a half-marathon, yes, but it also could include the more minor positive feelings from a brisk 30-minute jog or even a walk.

The endorphins and cannabinoids we produce in our brains, which contribute to pain reduction and to feelings of euphoria, play a role in the effect. A 2008 study found that two hours of running increased endorphin levels in athletes’ brains. And higher levels of endorphins were associated with stronger feelings of euphoria. Chaouloff and his colleagues have shown that removing cannabinoid receptors in the brains of mice decreases their running. In humans and dogs, Raichlan’s group has shown that 30 minutes of running boosts blood levels of the brain’s natural cannabinoid, anandamide.

The latest study adds leptin to the mix. Leptin is usually thought of as a hormone that regulates eating. Receptors for this fat hormone are found all over the brain. They are even found in the ventral tegmental area, a brain region that contains dopamine neurons, active in times of reward and reinforcement. Some of these neurons have leptin receptors. Knowing this, Stephanie Fulton, a neuroscientist at the University of Montreal in Canada, set out to examine how stopping leptin function might affect a mouse’s response to tasty foods.

But leptin also affects how much an animal moves. When leptin levels are high, running behavior tends to be low, while lower leptin levels are associated with increased running. In marathon runners, lower leptin is even associated with a faster race.  When Fulton and her group carefully deleted the protein STAT3, which is activated by leptin, from the dopamine neurons, they got a surprise. “We were expecting to find a lot of changes in food intake, but when we looked at it, nothing came up,” she says.

Instead, mice without STAT3 just ran. And ran. Mice run quite a lot, if you give them the chance, “six to seven kilometers voluntarily per day,” Fulton says. But mice without STAT3 ran upwards of 11 kilometers per day, she says. While normal mice ceased running when given a leptin injection, mice without STAT3 just kept going, Fulton and her colleagues report September 1 in Cell Metabolism.

The results suggest that leptin, via STAT3, helps control running motivation in mice. “Running behavior is strongly affected by our metabolic state,” Fulton explains. “And that makes complete sense when you think about it, that leptin is serving as a signal.” She speculates that low leptin, a signal for low blood glucose or low fat stores, helps to stimulate food seeking, promoting the urge to get a move on.  

“I found [this study] very interesting because it was very complete, at the molecular, behavioral and neurochemical level,” Chaouloff says. “Especially if you go to the ancestral view that says we are running to find food, the relationship between feeding and locomotor activity and running, it’s really interesting.”

Leptin may be important because it’s involved in the motivation to start running, not the euphoric feelings associated with a good 20-miler. “I would put motivation first,” says Chaouloff. “People usually say the runner’s high only happens in athletes that perform very long distances, and if you are not motivated to do so already, you would never get the runner’s high.”

But neither leptin nor any other chemical is going to work alone. “The motivation to exercise is not a single protein, a single hormone, a single event,” notes Raichlen. “It’s a complex interaction. Opioids, endocannabinoids, dopamine, it’s an incredibly complex system.” He notes that leptin is another hormone in the mix, and it’s also one that makes sense. “It provides the foundations for why you might expect a link between hormones associated with appetite and hunger and the motivation to exercise.”

Opioids, cannabinoids, leptin and dopamine may all work together to produce and control our desire to run and to regulate the fun we get out of it. “The [chemicals] play a key role,” says Fulton. “But that’s really all we know. At this point we have no understanding of how these signals interact, which cell populations are important for modulating runner’s high.” But the new work is a step toward understanding the recipe for the neurobiological cocktail that keeps me, and millions of others, running back for more. 

Editor’s note: This post was updated on September 25, 2015, to clarify that leptin is a fat hormone, not a gut hormone.