Gene associated with thinness may play a role in resisting weight gain

Some people can remain slim easily, irrespective of their diet, while others might be dieting and working out at the gym to maintain their shape.

Image Credit: Monkey Business Images/Shutterstock.com

In a study published in the Cell journal on May 21^st, 2020, scientists used a genetic database of over 47,000 people in Estonia to detect a gene associated with slenderness that may play a key role in preventing weight gain in such metabolically healthy slim people.

The researchers showed that deleting this gene leads to thinner mice and flies, and found that this gene expression in the brain may play a role in controlling energy expenditure.

We all know these people: it’s around one percent of the population. 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. We thought, ‘Let’s just turn it around and start a new research field’. Let’s study thinness.”

Josef Penninger, Study Senior Author and Professor, Department of Medical Genetics, University of British Columbia

Penninger is also the Director of the Life Sciences Institute

Penninger’s research team examined the data retrieved from the Estonian Biobank, which comprises 47,102 people aged between 20 to 44 years old. The researchers compared the clinical data and DNA samples of healthy thin individuals with the normal-weight persons and identified the genetic variants that were unique to thin persons in the ALK gene.

The researchers already know that the ALK gene often mutates in different types of cancer, and it acquired a reputation as an oncogene, a gene that fuels the development of tumors.

The function of the ALK gene beyond cancer has continued to be elusive. However, this latest discovery indicates that the gene may act as a new thinness gene involved in weight-gain resistance.

The scientists also discovered that ALK-deficient mice and flies remained slim and were impervious to diet-induced obesity. In addition, in spite of having the same activity levels and diet as that of the normal mice, ALK-deficient mice have lower body fat and body weight.

The mouse studies performed by the researchers also implied that the ALK gene, which is highly expressed in the brain, plays a role there by instructing the fat tissues to burn more amount of fat from food.

According to the researchers, therapeutics that target this gene may help researchers to fight obesity in the days to come.

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. 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.”

Josef Penninger, Study Senior Author and Professor, Department of Medical Genetics, University of British Columbia

Additional studies will be needed to see if these inhibitors were effective for such a purpose. The team has also planned to study how these ALK-expressing neurons control the brain at a molecular level to promote thinness and balance metabolism.

The Estonian Biobank researched by the team was perfect due to its broad age range and robust phenotype data. However, one restriction for replicating these outcomes is that the biobanks that collect tissue samples and medical or biological data lack a universal standard in data collection, which makes comparability a definite challenge.

According to the researchers, they would have to confirm their findings with other data banks via meta-analysis.

Penninger added, “You learn a lot from biobanks. 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 researchers added that their work is special because of the way it combines the exploration of the genetic basis of thinness on a population- and genome-wide scale with in vivo studies of the gene’s function in flies and mice.

It’s great to bring together different groups, from nutrition to biobanking, to hardcore mouse and fly genetics. 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.”

Josef Penninger, Study Senior Author and Professor, Department of Medical Genetics, University of British Columbia