2 proteins show promise as targets for treating obesity

The human body has intricate methods for regulating fat storage and maintaining weight. But sometimes those mechanisms fail to work properly, particularly in the context of a high-fat diet, or they actually counteract attempts to lose weight. Two groups of scientists have identified two proteins that play different roles in promoting obesity. Both could be promising drug targets.

The first is a hormone called leptin, which is known to help control our desire to eat. It is released from white fat tissue and it acts on neural receptors in the brain's hypothalamus to stimulate the feeling of a full stomach. In people who are obese, leptin is still present in large amounts, but it fails to signal that feeling of satiety. An international team of researchers has figured out what's behind this decreased sensitivity to leptin.

The scientists found that mice fed a high-fat diet produce an enzyme called MMP-2, which appears to damage the leptin receptors on the surface of hypothalamus neuronal cells. This makes leptin unable to bind to those cells, and hence prevents the sensation of having a full stomach. When the researchers fed a high-fat diet to mice that were genetically modified to not produce MMP-2, they observed that the animals gained less weight. And their leptin receptors remained intact. 

The team, which included scientists from the University of California, San Diego, the Salk Institute, Tel Aviv University and Monash University, detailed their findings in Science Translational Medicine.

"We need to ask what other pathways, in addition to leptin and its receptors, undergo a similar destructive process and what the consequences might be," said Rafi Mazor, Ph.D., a professor of bioengineering at UC San Diego and the paper's first author, in a statement.

In a separate study published in Science Advances, a team at the University of Michigan and Vanderbilt University focused on another receptor protein, MC3R.  They discovered that mice engineered to lack the protein gain more weight than normal mice do when fed a high-fat diet, and they also lose more weight when subjected to fasting. Therefore, MC3R keeps "energy rheostasis," said Roger Cone, Ph.D., director of the University of Michigan Life Sciences Institute and senior author of the study, in a statement.

Cone and his colleagues discovered MC3R and a related protein, MC4R, in mouse brains in the mid-1990s. His team and others around the world determined that MC4R plays a role in determining the body's energy homeostasis. With this new study, they believe they've shown how the two proteins work together: MC3R sets boundaries for how far the energy balance can deviate in either direction before MC4R comes to rescue to restore balance.

MC4R is already targeted by anti-obesity drugs. Rhythm Pharma, for one, is developing an MCR4 agonist called setmelanotide to treat a form of inherited obesity. The drug previously produced positive data in pro-opiomelanocortin deficiency obesity and recently showed promise in three patients with leptin receptor deficiency obesity.

According to the University of Michigan and Vanderbilt team, their observations of MC3R's activity could explain why some people find it difficult to lose weight by eating less or exercising more. As MC3R senses the abnormality and restores energy to the normal levels, our bodies burn less energy and increase appetite.

"A drug that targets MC3R has the potential to work as a diet aid, by reducing the rigidity of that lower boundary," said Cone in a statement. "In many ways, it's an ideal drug target because it could enable people to keep the weight off when they improve their eating and exercise habits."

As for UC San Diego's Mazor and his collaborators, they plan to confirm their MMP-2 findings in human brain cells. Ultimately, they hope to design an MMP-2 inhibitor and investigate whether it can help people—especially those in the early stages of obesity—lose weight.

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