Most people who’ve lost weight know how hard it is to keep the pounds from returning.

But after a large and rapid weight gain, it is just as difficult to keep weight on, a new study of overfed mice has found.

The study also found evidence that an unknown hormone produced by fat cells may be responsible for the weight loss. The findings were published online June 21 in Cell Metabolism.

“We’re now looking for this signal and we hope that once it’s found, it will induce weight loss in more typical obese individuals who have gained weight slowly over time,” says the study’s senior author Anthony Ferrante, MD, PhD, the Tilden-Wegen-Bieler Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

Scientists long ago confirmed what most people who lose weight know first-hand: It is a struggle to keep excess weight off. But, several clinical studies have suggested that the opposite is also true: It is hard to maintain a higher body weight after excessive eating. In one study of the Massa people of Cameroon, researchers found that men who gain weight during ritual overfeeding—consuming more than 6,000 calories a day to gain 40 pounds or more over a few months—lose all the weight after the ritual ends, and they do so without any attempt at dieting or exercise.

The hormone leptin is known to defend body weight when weight is lost; Ferrante’s team wanted to see what defends body weight when weight is gained. Such studies are difficult to conduct in people, so his team developed a tube-feeding system to rapidly fatten mice.

In 2 weeks, the mice gained 50% of their body weight (which is equivalent to a 150-pound person gaining 16 pounds a day for 2 weeks). After the tube-feeding stopped—and the mice had free access to food—their weight rapidly dropped and returned to their previous weight within a couple of weeks.

“This shows us that mice, like people, will naturally return to their original body weight when weight is gained rapidly,” Ferrante says. “And we can use these mice to help us understand the physiology behind this process.”

Many researchers have believed that leptin is the signal that tells the brain to counteract weight gain, but Ferrante’s team found that leptin levels had no impact on weight loss.

“We believe there’s another factor coming from fat in overfed mice that tells the brain to reduce how much you’re eating,” Ferrante says.

Ferrante adds that the body’s defense against weight gain only seems to kick in when weight is gained rapidly. And supporting that idea, his team saw differences in fat tissue between mice that gained weight rapidly and those that gained weight more slowly over time.

“We think there’s a natural limit to fat, and when the fat senses that things have gone overboard, it sends a signal to the brain. When fat is gained slowly over time, the fat can probably adapt,” he says.