While some can die and hit the gym hard to keep in shape, certain people remain comfortably slender irrespective of what they eat.
Scientists using a genomic sample of more than 47,000 individuals in Estonia in a report released today (May 21, 2020) in the journal Cell to find a gene related to thinness that may play a role in preventing weight gain in such metabolically stable, slim men. We prove that deleting this gene contributes to smaller flies and mice, and note that its activity in the brain may be involved in controlling energy expenditure.
“We all know these people: it’s around one percent of the population,” says senior author Josef Penninger, the director of the Life Sciences Institute and professor of the department of medical genetics. “They can eat whatever they want and be metabolically healthy. They eat a lot, they don’t do squats all the time, but they just don’t gain weight.
“Everybody studies obesity and the genetics of obesity,” he says. “We thought, ‘Let’s just turn it around and start a new research field.’ Let’s study thinness.”
Penninger’s team looked at Estonian Biobank records, which involves 47,102 individuals aged 20 to 44. The researchers matched stable lean individuals’ DNA samples and clinical results with normal-weight people, and found genetic mutations that were specific to slim people in the ALK gene.
Scientists have recognized that the ALK gene sometimes mutates into various forms of cancer, so it has developed a notoriety as an oncogene, a gene that induces tumor growth. ALK ‘s function outside of cancer has been left uncertain. But this new result indicated that the gene could play a role in weight-gain resistance as a novel thinness gene involved.
The researchers have observed that flies and mice appeared lean without ALK, and were immune to diet-induced obesity. Furthermore, mice with removed ALK have lower body weight and body fat while having the same diet and exercise rates as regular mice. The mouse experiments of the team have indicated that ALK plays a role, which is strongly expressed in the brain, thus instructing the fat tissues to consume more fat from food. The researchers claim that potential therapeutics targeting the gene may help scientists combat 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,” says Penninger. “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.”
To order to see if such inhibitors are successful for this reason, more testing would be needed. The team also aims to research further how ALK-expressing neurons control the brain at a molecular level to manage metabolism and facilitate thinness.
Thanks to its wide age range and good phenotype data the Estonian Biobank the team analyzed was perfect. But one drawback to replicating such results is that biobanks collecting biological or medical data and tissue samples do not have a standardized data collection norm which makes comparability a challenge. The researchers claim they would have to validate their results by meta-analysis of other datasets.
“You learn a lot from biobanks,” says Penninger. “But, like everything, it’s not the ultimate answer to life, but they’re the starting points and very good points for confirmation, very important links and associations to human health.”
The team claims its research is remarkable in that it blends analysis of the genetic origin of thinness on a community- and genome-wide scale with in vivo analyzes of the gene role in mice and flies.
“It’s great to bring together different groups, from nutrition to biobanking, to hardcore mouse and fly genetics,” says Penninger. “Together, this is one story including evolutionary trees in metabolism, the evolutionary role of ALK, human evidence, and hardcore biochemistry and genetics to provide causal evidence.”
