Why can some people eat as much as they want, and still stay thin?
In a study published today in the journal Cell, Life Sciences Institute Director Dr. Josef Penninger and a team of international colleagues report their discovery that a gene called ALK (Anaplastic Lymphoma Kinase) plays a role in resisting weight gain.
We all know these people, who can eat whatever they want, they don't exercise, but they just don't gain weight. They make up around one per cent of the population. We wanted to understand why. Most researchers study obesity and the genetics of obesity. We just turned it around and studied thinness, thereby starting a new field of research."
Dr. Josef Penninger, senior author, professor in the department of medical genetics and a Canada 150 research chair
Using biobank data from Estonia, Penninger's team, including researchers from Switzerland, Austria, and Australia, compared the genetic makeup and clinical profiles of 47,102 healthy thin, and normal-weight individuals aged 20-44. Among the genetic variations the team discovered in the thin group was a mutation in the ALK gene.
ALK's role in human physiology has been largely unclear. The gene is known to mutate frequently in several types of cancer, and has been identified as a driver of tumor development. "Our work reveals that ALK acts in the brain, where it regulates metabolism by integrating and controlling energy expenditure," says Michael Orthofer, the study's lead author and a postdoctoral fellow at the Institute of Molecular Biology in Vienna.
When Penninger's team deleted the ALK gene in flies and mice, both were resistant to diet-induced obesity. Despite consuming the same diet and having the same activity level, mice without ALK weighed less and had less body fat.
As ALK is highly expressed in the brain, its potential role in weight gain resistance make it an attractive mark for scientists developing therapeutics for obesity.
The team will next focus on understanding how neurons that express ALK regulate the brain at a molecular level, and determining how ALK balances metabolism to promote thinness. Validating the results in additional, more diverse human population studies will also be important.
"It's possible that we could reduce ALK function to see if we did stay skinny," says Penninger. "ALK inhibitors are used in cancer treatments already, so we know that ALK can be targeted therapeutically."
Orthofer, M., et al. (2020) Identification of ALK in Thinness. Cell. doi.org/10.1016/j.cell.2020.04.034.