Scientists have identified the function of a protein that has been confounding metabolism researchers for more than two decades. And it may have implications both for treating obesity and for understanding weight gain during pregnancy and menopause.

The protein, called the melanocortin 3 receptor (MC3R) maintains what senior author has termed "energy rheostasis," a poorly understood phenomenon in the field of metabolism research.

A lack of MC3R has almost no effect on mice under normal conditions. But when their metabolism is challenged, mice without this protein lose more weight when fasting and gain more weight when eating a high-fat diet, compared with normal mice. "This finding deepens our understanding of how energy balance is regulated," said senior author on the Science Advances study that details the findings.

Our bodies have mechanisms to balance the amount of energy we take in, through food consumption, and the amount of energy we use. When we lose weight, the brain increases hunger and signals the body to conserve energy. If we are using less energy, the brain sends signals to reduce food intake. This so-called energy homeostasis, or balance, is controlled in part by another receptor protein that  research group discovered, the melanocortin 4 receptor (MC4R).

Just like a rheostat on the wall determines how much energy goes into a light bulb, rheostasis in this case sets the upper or lower boundaries for how far the energy balance can shift before the MC4R protein will take action to restore the balance. When the body experiences some sort of 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.

This role in rheostasis 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. This lower boundary is what makes it difficult to keep weight off," said lead study author.

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

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

https://news.umich.edu/receptor-protein-in-the-brain-controls-the-bodys-fat-rheostat/
 
http://advances.sciencemag.org/content/4/8/eaat0866