Protein discovery may help to develop treatments for metabolic disorders

metabolic disorders
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Scientists have identified a potentially game-changing protein known as augmentor-alpha that regulates body weight, which might be crucial in designing novel treatments for metabolic disorders.

Performed by researchers at Yale University, the new rodent study illuminated the essential role of augmentor-alpha in controlling body weight, a protein that is also understood to be instrumental in cancer. Augmentor-alpha binds to and activates the anaplastic lymphoma kinase receptor (ALK), a molecule that, if mutated, can cause a range of cancers, such as paediatric neuroblastoma, B-cell lymphomas, and certain lung cancers. Now, Yale experts believe the protein could be the key to treating metabolic disorders.

The study findings have been published in the Proceedings of the National Academy of Sciences.

How does augmentor-alpha work?

To understand augmentor-alpha in more detail, the researchers first intended to establish where the protein is located, finding that in mice, augmentor-alpha was most significantly expressed in the hypothalamus brain region. They discovered that it was expressed within cells called agouti-related peptide (AgRP) neurons, which promote feelings of hunger.

Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine and an author of the study, commented: “AgRP neurons are so important for feeling hunger that without them, you would not eat. You would die. So, when it became clear that augmentor-alpha was dominantly expressed in these neurons, it immediately suggested that augmentor-alpha was involved in metabolism.”

Moreover, the team uncovered further evidence of an association between metabolism and augmentor-alpha when they demonstrated that fasting increases augmentor-alpha expression in these neurons.

Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology, co-director of the Yale Cancer Biology Institute, and senior author of the study, said: “Fasting appeared to be a signal to make more of this protein.”

Subsequently, the researchers analysed mice that lacked augmentor-alpha, observing that compared to typical mice, those without the protein were thinner regardless of if they ate a standard or high-fat diet. They were also more physically active than ordinary mice but did not eat significantly more food, which most likely caused their thinness.

When mice lack food, they will typically conserve energy and reduce their physical activity; however, during fasting, the mice without augmentor-alpha remained very active, suggesting that the protein is a vital 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 is a lack of food. It is like it is saying, ‘You do not have food, do not expend so much energy.'”

Developing treatments for metabolic disorders

The team hypothesised that due to its association with metabolism, inhibiting or enhancing augmentor-alpha could help treat an array of metabolic disorders. There are various drugs that inhibit augmentor-alpha, such as cancer medications that target ALK, that could be repurposed to combat metabolic disorders where excess weight can increase disease.

The team believes that increasing the protein’s effects might provide a treatment option for people experiencing harmful weight loss, such as those with anorexia, cachexia, or persistent loss of appetite due to the side effects of a drug or injury.

The team has recently identified the structure of ALK and how it interacts with augmentor-alpha, comparing the protein with insulin that is produced in the pancreas but has effects throughout the body. In contrast, augmentor-alpha is produced in AgRP neurons in the hypothalamus and influences other nearby neurons.

“It acts very locally within the hypothalamus,” said Schlessinger.

The hypothalamus controls a variety of vital functions, such as reproduction, temperature regulation, and stress response. Furthermore, the role of augmentor-alpha within the hypothalamus means it could be involved in some of these processes too.

Schlessinger concluded: “I think we are just scratching the surface of augmentor-alpha’s role.”

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