Yale scientists have uncovered its role in regulating body weight by studying the correlation of a protein called augmentor-alpha with cancer. The protein binds to and activates the anaplastic lymphoma kinase receptor (ALK) molecule. Mutation of this molecule causes a wide range of cancers.
To determine the role of this protein, scientists first pinpointed its location. In mice models, they found that the protein augmentor-alpha is most strongly expressed in the brain’s hypothalamus region. More specifically, they found that it is expressed in cells called agouti-related peptide (AgRP) neurons, known to promote hunger.
AgRP neurons are a small population of cells in the arcuate nucleus of the hypothalamus that are critical for regulating food intake.
Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine and an author of the study, said, “So when it became clear that augmentor-alpha was dominantly expressed in these neurons, it immediately suggested that augmentor-alpha was involved in metabolism.”
When scientists observed that fasting increased the expression of augmentor-alpha in these neurons, they found further evidence of a link between augmentor-alpha and metabolism.
Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology, said, “Fasting appeared to signal to make more of this protein.”
Scientists studied mice that lacked the protein altogether. Compared to typical mice, those without augmentor-alpha were thinner, whether they ate a normal or a high-fat diet. They were also more physically active than typical mice but did not eat significantly more food, likely contributing to their thinness.
When faced with a lack of food, mice will typically conserve energy and reduce their physical activity. But during fasting, mice without augmentor-alpha were still very active. This suggests that the protein is an essential signal for energy conservation.
Schlessinger said, “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. It’s like it is saying, ‘You don’t have food, don’t expend so much energy.'”
Scientists noted, “This link to metabolism suggests inhibiting or enhancing augmentor-alpha’s effect could be useful for several 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 the 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.”
Previously, scientists had discovered the structure of ALK and determined how it interacts with augmentor-alpha. This new study supports and adds to what they observed in this earlier research.
The findings were published on April 11 in the Proceedings of the National Academy of Sciences.