Receptor protein in the brain controls the body's fat 'rheostat'

August 22, 2018, University of Michigan
Credit: CC0 Public Domain

Scientists at the University of Michigan and Vanderbilt University 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 Roger Cone, director of the U-M Life Sciences Institute, has termed " 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 , compared with .

"This finding deepens our understanding of how is regulated," said Cone, senior author on the Science Advances study that details the findings. The discovery, he adds, opens new doors for developing anti-obesity drugs.

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 Cone's 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 Masoud Ghamari-Langroudi of the Vanderbilt University School of Medicine.

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

While at Vanderbilt, co-author Rachel Lippert of the Max Planck Institute for Metabolism Research 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.

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, fairly quickly determined MC4R's role in maintaining the setpoint 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 , in contrast, sometimes led to excessive loss and other times to excessive .

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

Explore further: Researchers find a novel signaling pathway involved in appetite control

More information: "Regulation of energy rheostasis by the melanocortin-3 receptor" Science Advances (2018). advances.sciencemag.org/content/4/8/eaat0866

Related Stories

Researchers find a novel signaling pathway involved in appetite control

January 20, 2015
A new study has revealed important details of a molecular signaling system in the brain that is involved in the control of body weight and metabolism. The study, published January 19 in Nature, provides a new understanding ...

New study finds that fat consumption is the only cause of weight gain

July 13, 2018
Scientists from the University of Aberdeen and the Chinese Academy of Sciences have undertaken the largest study of its kind looking at what components of diet—fat, carbohydrates or protein—caused mice to gain weight.

Receptor proteins that respond to nicotine may help fat cells burn energy

May 21, 2018
The same proteins that moderate nicotine dependence in the brain may be involved in regulating metabolism by acting directly on certain types of fat cells, new research from the University of Michigan Life Sciences Institute ...

Appetite-controlling molecule could prevent 'rebound' weight gain after dieting

February 15, 2018
Scientists have revealed how mice control their appetite when under stress such as cold temperatures and starvation, according to a new study by Monash University and St Vincent's Institute in Melbourne. The results shed ...

Voluntary exercise and energy balance

March 23, 2018
Physical exercise alone generally fails to produce meaningful weight loss in obese individuals, and reduced non-exercise activity has been suggested to explain this observation.

Recommended for you

New inflammation inhibitor discovered

November 16, 2018
A multidisciplinary team of researchers led from Karolinska Institutet in Sweden have developed an anti-inflammatory drug molecule with a new mechanism of action. By inhibiting a certain protein, the researchers were able ...

Gut hormone and brown fat interact to tell the brain it's time to stop eating

November 15, 2018
Researchers from Germany and Finland have shown that so-called "brown fat" interacts with the gut hormone secretin in mice to relay nutritional signals about fullness to the brain during a meal. The study, appearing November ...

Brain, muscle cells found lurking in kidney organoids grown in lab

November 15, 2018
Scientists hoping to develop better treatments for kidney disease have turned their attention to growing clusters of kidney cells in the lab. One day, so-called organoids—grown from human stem cells—may help repair damaged ...

How the Tasmanian devil inspired researchers to create 'safe cell' therapies

November 15, 2018
A contagious facial cancer that has ravaged Tasmanian devils in southern Australia isn't the first place one would look to find the key to advancing cell therapies in humans.

Researchers discover important connection between cells in the liver

November 15, 2018
University of Minnesota Medical School researchers have made a discovery which could lead to a new way of thinking about how disease pathogenesis in the liver is regulated, which is important for understanding the condition ...

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.