A mutation and a mystery: Weight gain without a change in energy use

Why did the mouse on the left put on so much weight?
Could the tendency toward weight gain in the mouse at left help explain some human obesity?
Two mice scurry around in an enclosure crossed through with light beams. The beams track their movement to measure their energy expenditure, along with the amount of oxygen they breathe in and carbon dioxide they exhale. The mice, who are siblings, are equally active and are held to the same diet, but there’s one critical difference: One mouse is noticeably heavier than the other.

“These [heavier] mice aren’t burning the fat,” says Joseph Majzoub, MD, chief of endocrinology at Boston Children’s Hospital. “They’re somehow holding onto it.”

In fact, the mice have to be underfed by 10 to 15 percent just to stay as slim as their siblings. Their experiences seem to parallel those of people who complain of gaining weight even when they don’t eat more than others. When allowed to eat as much as they want, the mice quickly begin to eat three to four times as much as the others and balloon to more than twice their size.

These heavier mice are knockouts—that is, one of their genes has been rendered inactive. That gene is Mrap2, and Majzoub is exploring its connection to appetite, energy expenditure and severe obesity. As they report in the July 19 Science, Majzoub and collaborators have also found corresponding genetic mutations in a cohort of obese humans, affecting four individuals with severe, early-onset obesity.

“There are some people who get obese in our environment of abundant, high-calorie foods, and some people who don’t. That is likely due to genetic differences among people who are exposed to the same environment.”

Without Mrap2, and possibly without its human counterpart MRAP2, the signal to decrease appetite as a result of having enough food has trouble getting through. Majzoub’s mouse work has shown that the proteins encoded by these genes help activate a receptor, Mc4r, that is associated with metabolism and appetite. Other mutations along this signaling chain, which starts with fat cells producing the hormone leptin, are known to increase the likelihood of obesity.

Majzoub’s mice became obese whether the gene was knocked out in just the brain or their whole bodies. They gained the most weight when both copies of Mrap2 were knocked out, but still gained weight and had an increase in appetite with one working copy of the gene.

Weight gain in the Mrap2 knockout mice, when fed 15% fewer calories than normal, closely matches that of normal mice on an unrestricted diet. At the point marked by the upward arrow (⬆) some knockout mice are switched to unlimited food and show dramatic weight gain.
Weight gain in the Mrap2 knockout mice, fed 15% fewer calories than normal, closely matches that of normal mice on an unrestricted diet. At the point marked by the upward arrow (⬆), some knockout mice are switched to unlimited food and show dramatic weight gain.
When given a high-fat diet, the knockout mice showed much more rapid weight gain than the normal mice. Again, Majzoub finds this interesting in the context of the rapid rise in human obesity in recent decades, and speculates that the unhealthy foods all around us might be especially toxic in people with particular genetic dispositions.

The human counterpart

Majzoub collaborated with Sadaf Farooqi, MD, PhD, of the University of Cambridge, and others to investigate groups of severely obese patients from around the world—including many from the U.K., and, to a lesser extent, Sweden. The mutations affecting the four people in the obese cohort were severe; in one case, these mutations prevented the MRAP2 protein from forming entirely. But Majzoub suspects that milder MRAP2 mutations also might contribute to obesity in combination with other factors, like food environment.

“There’s been a tremendous increase in the incidence and prevalence of obesity over the past 20 years, and our genes certainly haven’t changed during that time period,” Majzoub says. “But there are some people who get obese in our environment of abundant, high-calorie foods, and some people who don’t. That is likely due to genetic differences among people who are exposed to the same environment.”

Why the mice initially gained weight when held to the same diet—despite apparently similar energy expenditure—remains a mystery. Majzoub suggests a connection to the thrifty-gene hypothesis, which posits that energy-conserving mutations that cause obesity today exist because they are beneficial to humans in times of famine.

Majzoub’s group can’t tell yet if the human mutations produce the more-gain-with-less-food effect that the mice experienced early on in their life cycle: “If we can identify humans with the gene early enough,” Majzoub says, “maybe we can ask whether the same is true for them.”