Targeting a gene called ALK may prevent weight gain and could lead to effective therapies to combat obesity, a large study in humans and animals suggests.
Genetics play a substantial role in obesity development. In recent years, studies have identified diverse genes that regulate body weight, but most research has focused on excess weight, not thinness.
“Most researchers study obesity and the genetics of obesity,” Josef Penninger, PhD, a professor at the University of British Columbia and the study’s senior author, said in a press release. “We just turned it around and studied thinness, thereby starting a new field of research.”
With collaborators from Switzerland, Austria, and Australia, Penninger’s team first used data from an Estonian biobank to conduct a genome-wide association study (GWAS). GWAS involves looking for genetic variations that are significantly more common among individuals with a given condition or trait — in this case, thinness, as defined by a low body mass index (BMI), which is a ratio of weight to height.
What constitutes a “thin” BMI varies substantially based on factors such as age and sex. The researchers defined thinness for the purposes of the study as a BMI below the sixth percentile adjusted for age and sex. Generally, this corresponds to a BMI lower than 18 kg/m2. For comparison, the researchers defined a normal BMI as being between the 30th and 50th percentiles and obesity as the highest 95th percentile.
In total, the study analyzed 881 individuals characterized as thin, 3,173 with a normal BMI, and 555 characterized as obese, ages 20–44 in all groups. People with health conditions that could affect body weight, such as lipodystrophy or anorexia nervosa, were not included in the analysis.
The GWAS analysis found a mutation in ALK in the thin group. This gene has been extensively studied as a driver of cancer development, but little is known about its other functions.
By design, GWAS is only able to show statistical associations, not cause-and-effect relationships. As such, the investigators used animal models to test whether ALK is a candidate thinness gene.
First, they reduced the expression of ALK in fruit flies. This led to decreased levels of triglycerides (fat), although the flies consumed normal amounts of food. Increasing ALK expression did not affect triglyceride levels.
The researchers then examined mice that had been engineered to lack ALK. The mice had no apparent abnormalities in fertility, behavior, and food intake. Yet, starting around 5 weeks of age, ALK-deficient mice weighed significantly less than mice with functional ALK, and these differences persisted throughout adulthood.
“These results, in line with our human GWAS and fly data, show that [ALK-deficient] mice on standard chow diet exhibit a thin phenotype,” the researchers wrote.
Additional analyses suggested that mice lacking this gene had increased energy expenditure. This finding suggested that a lack of ALK could prevent weight gain. To test the idea, the researchers used two mouse models of obesity: one in which mice were fed a high-fat diet, and one of genetic obesity caused by a mutation in the LEP gene, which provides instructions for making the hormone leptin.
In both models, lacking ALK led to significantly less weight gain than in animals with the normal gene.
“Thus, Alk-deficient mice exhibit increased energy expenditure and are markedly protected against [high fat diet]- and genetically induced obesity,” the researchers wrote.
Additional experiments to better determine the link between ALK and weight revealed that the gene was particularly important in the brain to help regulate how fat is burned. High levels of ALK expression were found in the hypothalamus, an area of the brain area key in energy balance.
“Our work reveals that ALK acts in the brain, where it regulates metabolism by integrating and controlling energy expenditure,” said the study’s first author Michael Orthofer, PhD a postdoctoral fellow at the Institute of Molecular Biotechnology in Vienna.
These findings suggest that blocking the activity of ALK could be a strategy for promoting weight loss.
“It’s possible that we could reduce ALK function to see if we did stay skinny,” Penninger said. “ALK inhibitors are used in cancer treatments already, so we know that ALK can be targeted therapeutically.”
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