Scientists at the University of Michigan and Vanderbilt University have identified the function of a protein that has puzzled metabolism researchers for more than two decades.

And the discovery, studied in mice, may have implications both for treating obesity and for understanding weight gain during pregnancy and menopause.

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A protein known as the melanocortin 3 receptor (or MC3R) maintains what Roger Cone, Ph.D., has termed "energy rheostasis" — in other words, the limits of how far an energy surplus or deficit can go before the body will try to bring energy back to its balance point.

A lack of MC3R has almost no effect on mice under normal dietary conditions.

But when their metabolism is challenged, researchers have learned, mice without this protein lose more weight when fasting and gain more weight when eating a high-fat diet compared with normal mice.

The reason: Our bodies have mechanisms to balance the amount of energy we take in through food consumption and the amount of energy we use. But those mechanisms need a signal to let them know when the energy levels are out of balance. MC3R provides that signal.

When we lose weight, the brain increases hunger and signals the body to conserve energy. If we're using less energy, the brain sends signals to reduce food intake.

This so-called energy homeostasis, or balance, is regulated in part by another receptor protein that Cone's research group also discovered two decades ago, the melanocortin 4 receptor, or MC4R.

But until now, the function of MC3R was not well understood.

"This finding deepens our understanding of how energy balance is regulated," says Cone, director of the U-M Life Sciences Institute and senior author on the Science Advances study that details the findings.

The discovery, he adds, opens new doors for developing anti-obesity drugs.

New drug benchmark targeted

Just like a rheostat on the wall determines how much energy goes into a lightbulb, rheostasis in the body sets the upper or lower boundaries for how far a person's energy balance can shift before the MC4R protein will take action to restore the balance.

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When the body experiences metabolic stress that shifts energy levels — fasting or eating a high-fat diet, for example — MC3R ensures that the balance of energy and fat in the body does not drift too far in either direction.

Discovery of this function makes MC3R a promising new drug target for treating obesity.

"When we eat less and exercise more to lose weight, our bodies sense when the energy balance has tipped below the established lower boundary and try to adjust by using less energy and increasing appetite to return to homeostasis," says lead study author Masoud Ghamari-Langroudi, M.D., Ph.D., of the Vanderbilt University School of Medicine.

"This lower boundary is what makes it difficult to keep weight off."

A drug that targets MC3R has the potential to work as a diet aid by reducing the rigidity of that lower boundary.

"In many ways, it's an ideal drug target because it could enable people to keep the weight off when they improve eating and exercise habits," Cone says.

Discovery offers potential, hope

The MC3R protein also plays a role in regulating changes in the body's energy balance that occur as part of the normal life cycle. During pregnancy and menopause, for example, women experience an increase in the fat reserves stored in the body.

While at Vanderbilt, Rachel Lippert, Ph.D., made the unusual discovery that mice lacking the MC3R protein gain less weight than they should during pregnancy and gain more weight than normal mice during a mouse model of menopause.

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These seemingly contradictory effects are why the protein perplexed researchers for so long.

Cone and his colleagues discovered both MC3R and MC4R in mouse brains in the mid-1990s. The researchers, along with other laboratories around the world, quickly determined MC4R's role in maintaining the set point for energy homeostasis. A lack of MC4R is now known to be the most common cause of syndromic obesity in humans.

Scientists did not understand why the MC3R protein, in contrast, sometimes led to excessive weight loss and other times to excessive weight gain.

"And now," Cone says, "we finally we have an answer."