Extraordinary insight has has been collected over the past few years into the genetic driver that supports obesity, but there is little research focused on genes that can be associated with thinness. A comprehensive new study investigating the potential of “thin” genes has identified one gene in particular that seems to play a major role in promoting thinness in humans and animals.
“We all know these people, who can eat whatever they want, they don’t exercise, but they don’t gain weight,” said Josef Penninger, senior author of the new study. “They make up about one percent of the population. We want to understand why. Most researchers study obesity and obesity genetics. We just play it and study thinness, so we start a new field of research. “
The research began by conducting a study of large genome-wide associations consisting of nearly 50,000 subjects from Estonian biobank data. Instead of comparing lean and obese subjects, the profile looks at genetic differences between healthy, thin individuals and normal weight individuals.
Two special variants of the ALK gene quickly stood out to researchers. Early tests on animals revealed completely blocking the activity of genes that provide resistance to obesity due to diet. Mice lacking the ALK gene seem to burn more calories and break down fat faster.
“By using a technique called indirect calorimetry, we can show that mice lacking ALK show increased energy expenditure,” said Michael Orthofer, the first author of the study. “This means that they burn more calories than normal mice and explain why they stay thin even if they eat the same amount. In addition, these animals also showed increased glucose tolerance. “
Zooming in further, to understand what mechanisms play a role, the researchers found ALK is highly expressed in certain brain regions in the hypothalamus known as the paraventricular nucleus (PVN). When ALK is blocked in this single brain region alone, researchers see the same weight reduction and general metabolic effects as detected in full knockout animals.
What makes this discovery a little more interesting than the discovery of other genes is that there are a number of studies that have accumulated around ALK inhibition in humans. For several years ALK has been investigated as a major driver of cancer development. In fact, several ALK inhibitors have been developed, initially targeting non-small cell lung carcinoma.
Various ALK inhibitors have been approved by the FDA for clinical use, plus many others are at different stages of the trial. So, as Penninger suggested, not only is ALK proven to be therapeutically targeted, many drugs currently exist to do the job.
“If you think about it, it’s realistic that we can turn off ALK and reduce the function of ALK to see if we stay thin,” he said. “ALK inhibitors are already used in cancer treatment. This can be targeted. We might be able to inhibit ALK, and we will actually try to do this in the future.”
This new study was published in a journal Cell.
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