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Scientists find a fat hormone toggles a runner’s high

A long run feels the worst until it feels the best. That’s primarily thanks to the runner’s high — those euphoric feelings that strike halfway through an endurance workout.

Now, researchers have charted what happens to the brain to produce a runner’s high. The sensation is tied to low levels of leptin — a brain hormone that tempers food consumption when you’ve had enough to eat, according to a study published today in the journal Cell Metabolism. The scientists sketch out a switch in a precise set of brain cells that drives the urge to run in mice. Leptin regulates this switch, causing the animals to seek opportunities to run as well as allowing them to run for twice as long as usual.

Leptin is a “fat hormone” that tells your mind that you’re full of food. When you eat, leptin levels rise and you become lethargic. In contrast, when animals lose leptin in their brains, they become hyperactive gluttons, uncontrollably seeking and consuming food. They can’t be sated.

However, this low-leptin turbo boost is seen in another scenario: endurance runners. Marathon runners tend to eat less, which reduces the amount of leptin in their bodies. An earlier study found that marathon runners with the lowest leptin run faster and take the least time to complete their races, regardless of their body mass index. Rodents run faster and longer with less leptin, too. These trends suggest that leptin may govern the will to run, but how?

The new study shows that leptin toggles a runner’s desire by cutting access to a reward chemical — dopamine — in one of the brain’s motivation centers, the ventral tegmental area. Dopamine in the ventral tegmental area promotes the sensations of elation and satisfaction felt after eating a big meal or having sex.

But leptin doesn’t act alone. A protein called STAT3 is an intermediary in this leptin-based running switch. Leptin and STAT3 are molecular buddies. When leptin hormone soaks neurons in the brain, STAT3 is produced inside the cells, but when leptin levels fall, so too does STAT3.

Falling STAT3 levels are a runner’s version of a green light, according to this new study from the University of Montreal. When the team genetically deleted STAT3 from the ventral tegmental area in mice, the rodents “jogged” 6.8 miles per day on their cage’s running wheel — nearly twice as much as the average for a normal mice, or 3.7 miles per day. When put into a cage with two separate chambers — one with a regular running wheel and one with a broken wheel — the STAT3-deficient mice spent more time in the working “exercise room” than normal mice, even if they weren’t running.

The researchers found that losing STAT3 blunted dopamine levels in the mice’s ventral tegmental area. A dopamine drop in the ventral tegmental area can trigger reward-seeking in humans. So, the team argues that marathon runners are reward seekers driven by low levels of leptin and STAT3.

“Our study suggests that people with lower fat-adjusted leptin levels, such as high-performance marathon runners, could potentially be more susceptible to the rewarding effects of running and thus possibly more inclined to exercise,” said neuroscientist Stephanie Fulton of the University of Montreal in a press statement.

In other words, a hormone behind the urge to eat — leptin — also controls the desire to run, according to their findings. Humans and animals may have evolved this switch to maintain their energy levels for hunting at times when food was scarce.

“We think that a fall in leptin levels increases motivation for physical activity as a means to enhance exploration and the pursuit of food,” Fulton said, though she admits other metabolic signals outside of leptin might be involved in the runner’s high, too.

Her team plans to look for those signals while peering into whether leptin triggers other aspects of a runner’s high, such as better muscle stamina or the pain relief caused by the release of natural opioid chemicals.

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