This cancer-related gene may also hold the key to beating obesity

Obesity
A recent study of people who are resistant to weight gain has linked variants in the ALK gene to thinness. (Wikimedia Commons/Wellcome Trust)

We all know those people. They eat whatever they want, rarely exercise and still never seem to gain weight. Now, scientists may have found a gene that may keep these lucky folks thin—and it’s a well-known cancer-related gene.

After analyzing a database of healthy people, an international team of scientists led by the University of British Columbia in Canada found that some variants in the ALK gene are linked to a low susceptibility to weight gain in naturally thin people, according to a new study published in Cell. Mice genetically modified to lack the ALK gene also showed a marked resistance to obesity.

The protein the ALK gene encodes for plays a key role in cell communication and the development and function of the nervous system. Mutations of the ALK gene have been linked to non-small cell lung cancer and neuroblastoma. Drugs that block these mutated versions of the gene, including Pfizer’s Xalkori and Lorbrena, Novartis’ Zykadia, Roche’s Alecensa and Takeda’s Alunbrig, have been used to fight ALK-driven tumors.

Rather than focusing on risk factors in obese individuals, the authors of the new study started by looking at slim people. They scoured the database, which contains data from over 47,000 healthy people in Estonia, for genetic clues linked to thinness. They specifically analyzed the genetic features of people with a body mass index below 18 kg/m2.

They found two particular variants in the ALK gene that are different from known cancer-driving mutations and are linked with thinness. Then they tried knocking down the equivalent gene in flies. That led to significantly lower fat levels in the blood, the team found.

They went on to study ALK’s role in mice, comparing animals that had their ALK gene depleted with controls. Both groups had the same food intake, daily activity and intestinal lipid absorption, but the ALK-knockout mice exhibited reduced weight gain and improved glucose tolerance.

What’s more, challenging these rodents with a high-fat diet showed that ALK-knockout mice were protected from significant weight gain, while the normal mice became obese. Mice without ALK seemed to burn calories at higher levels, the team reported. Further analysis suggested that ALK, which is highly expressed in the brain, may play a part in instructing the fat tissues to burn more energy.

RELATED: Could blocking a single gene cure obesity without diet and exercise?

Scientists have been probing the genome for inspirations to fight obesity. A team led by Flinders University in South Australia previously found removing the RCAN1 gene kept mice from gaining weight. Researchers at the Washington University School of Medicine in St. Louis used a gene that makes the protein follistatin to help build muscle mass in mice and prevented obesity. Rhythm Pharmaceuticals recently reported positive phase 3 data of its melanocortin-4 receptor agonist setmelanotide in patients with a type of genetic obesity.

Authors of the current Cell study suggest treatments targeting ALK might help fight obesity. “If you think about it, it's realistic that we could shut down ALK and reduce ALK function to see if we did stay skinny,” the study’s senior author, Josef Penninger at the University of British Columbia, said in a statement. “ALK inhibitors are used in cancer treatments already. It’s targetable. We could possibly inhibit ALK, and we actually will try to do this in the future.”

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