Yale Team Identifies Weight-Regulating Protein

Yale scientists have discovered that a protein known to play a role in certain cancers also regulates body weight in mice, an insight that could lead to new treatments for metabolic disorders.

The protein, augmentor-alpha, is known to bind to and activate anaplastic lymphoma kinase receptor (ALK). When mutated, ALK drives a variety of human cancers, including pediatric neuroblastoma, B-cell lymphomas, and certain lung cancers.

The team set out initially to understand augmentor-alpha and the role it plays in the body. In doing so, they found that it is most strongly expressed in the hypothalamus region of the brain, and especially in agouti-related peptide (AgRP) neurons, which are known to promote hunger. “AgRP neurons are so important for feeling hunger that without them, you wouldn’t eat. You’d die,” says Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine and study coauthor. “So, when it became clear that augmentor-alpha was dominantly expressed in these neurons, it immediately suggested that augmentor-alpha was involved in metabolism.”

They also found further evidence of a link between augmentor-alpha and metabolism when they observed that fasting increased the expression of augmentor-alpha in these neurons. “Fasting appeared to be a signal to make more of this protein,” says Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology, co-director of the Yale Cancer Biology Institute, and study coauthor.

Digging further, they found that mice that lacked the protein altogether were thinner—even when fed a high-fat diet—than typical mice. They were also more physically active than typical mice, but did not eat significantly more food. Additionally, mice without augmentor-alpha were still very active when faced with a lack of food, which is the opposite of typical behavior. This suggests the protein is also an important signal for energy conservation.  “From what we observed in this study, we think one of augmentor-alpha’s roles in the body is to slow down metabolism when there’s a lack of food,” says Schlessinger. “It’s like it is saying, ‘You don’t have food, don’t expend so much energy.’”

This link to metabolism suggests inhibiting or enhancing augmentor-alpha’s effect could be useful for a number of diseases. Drugs that inhibit augmentor-alpha, which certain cancer drugs that target ALK do, could be repurposed for metabolic disorders where excess weight can exacerbate disease. And the enhancement of augmentor-alpha’s effect might offer a treatment option for people experiencing harmful weight loss, such as those with anorexia, cachexia, or persistent loss of appetite due to drug side effects or injury.

Previous work at Yale that included Schlessinger uncovered the structure of ALK and how it interacts with augmentor-alpha. Schlessinger said the new findings support and add to what they observed in this earlier research. He compared augmentor-alpha to insulin, which is produced in the pancreas but has effects throughout the body. Conversely, augmentor-alpha is produced in AgRP neurons in the hypothalamus and affects other nearby neurons. “It acts very locally within the hypothalamus,” said Schlessinger. And because the hypothalamus controls many essential functions, including reproduction, temperature regulation, and stress response, augmentor-alpha’s effect within the hypothalamus means it could be involved in some of these other processes as well. “I think we’re just scratching the surface of augmentor-alpha’s role,” said Schlessinger.

The findings were published in the Proceedings of the National Academy of Sciences.