Rather than focusing on risk factors in obese individuals, the authors of the new study started by looking at slim people.
Why can some people eat as much as they want, and still stay thin? Now, scientists may have found a gene that may keep these lucky folks thin-and it's a well-known cancer-related gene.
Zooming in even further, to understand exactly what mechanisms were at play, the researchers found ALK to be highly expressed in a particular brain region in the hypothalamus known as the paraventricular nucleus (PVN).
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.
But one promising aspect of the discovery is that scientists already know how to inhibit ALK in humans because of its role in cancer development, so testing the link further is doable.
A Vancouver-based scientist, together with a team of global researchers, says he's identified a gene mutation that may help some people stay thin.
When the scientists removed this gene from mice, they could feed them a high-fat diet without causing the animals to pile on the pounds. Moreover, regardless of having a similar diet and activity levels as normal mice, mice with deleted ALK have lower body weight and body fat. When ALK was blocked in this single brain region only, the researchers saw the same body weight reductions and general metabolic effects as detected in the full ALK knockout animals.
"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", he says.
Drugs already exist which do this, because the ALK gene is also linked to cancer.
The research began by conducting a large genome-wide association study comprising almost 50,000 subjects from Estonian biobank data.
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.
The potential is that therapeutics targeting this gene might help fight obesity in the future, but more work is needed. The team says its findings need to be confimed through a meta-analysis with other data banks. "You learn a lot from biobanks", says Penninger. "It's great to bring together different groups, from nutrition to biobanking, to hardcore mouse and fly genetics", says Penninger.
Reference: "Identification of ALK in thinness" by Orthofer et al., 21 May 2020, Cell. W.H. was supported by a grant from the European Community's Seventh Framework Programme, the Research Institute of Molecular Pathology (IMP), Boehringer Ingelheim, the Austrian Research Promotion Agency, IMBA, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, an ERC Advanced Grant, and an Era of Hope Innovator award.