Great insights have been gathered over recent years into the genetic drivers underpinning obesity, but little study has focused on the genes that could be related to thinness. A comprehensive new study investigating potential "thin" genes has identified one gene in particular that seems to play a major role in promoting thinness in both humans and animals.
“We all know these people, who can eat whatever they want, they don’t exercise, but they just don’t gain weight,” says Josef Penninger, senior author on the new study. “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.”
The research began by conducting a large genome-wide association study comprising nearly 50,000 subjects from Estonian biobank data. Instead of comparing thin and obese subjects, the profile looked at the genetic differences between healthy, thin individuals and normal weight individuals.
Two particular variants in the ALK gene quickly stood out to the researchers. Initial tests in animals revealed entirely blocking activity of the gene conferred a resistance to diet-induced obesity. Mice deficient in the ALK gene seemed to burn more calories and break down fat more rapidly.
“By using a technique called indirect calorimetry, we could show that ALK deficient mice exhibit increased energy expenditure,” says Michael Orthofer, first author on the study. “This means that they burn more calories than normal mice and explains why they remain thin even if they eat the same amount of food. In addition to that, these animals also show improved glucose tolerance.”
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). 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.
What makes this discovery a little more exciting than other gene discoveries is that there is a volume of research already accumulated surrounding ALK inhibition in humans. For several years ALK has been investigated as a major driver of cancer development. In fact, several ALK inhibitors have already been developed, initially targeting non-small cell lung carcinomas.
A variety of ALK inhibitors have already been approved by the FDA for clinical uses, plus an assortment more are at different trial stages. So, as Penninger suggests, not only has ALK already been shown to be therapeutically targetable, many drugs currently exist to do the job.
"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. "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."
The new study was published in the journal Cell.
Sources: Austrian Academy of Sciences, University of British Columbia
