A recent genetic association study of people who are naturally thin has tied variants in the anaplastic lymphoma kinase (ALK) gene to thinness.

"We all know these people: it's around one percent of the population," Josef Penninger, senior author of the study and a researcher at the University of British Columbia, said in a statement. "They can eat whatever they want and be metabolically healthy."

More than 700 SNPs have been linked to body mass index (BMI), but only a handful of genes involved in body weight regulation have been identified. For their study, rather than focusing on risk of developing obesity as many previous studies have, Penninger and his colleagues searched for genetic variants associated with being thin. 

"Everybody studies obesity and the genetics of obesity," he said. "We thought, 'Let's just turn it around and start a new research field.' Let's study thinness." 

Through a genome-wide association study of metabolically healthy thin individuals from the Estonian biobank, they homed in on a variant in ALK. As they reported in Cell on Thursday, the researchers confirmed in fruit flies and mice that loss of the ALK gene protected the animals from obesity. 

Using samples from the Estonian biobank, Penninger and his colleagues conducted a genome-wide association study of thinness. They defined thin as individuals belonging to the lowest 6th percentile of age- and gender-adjusted BMI, after excluding individuals with conditions like lipodystrophy or anorexia nervosa. Just shy of 2 percent, or 881 people, of the biobank cohort were classified as thin, and the rest, 3,173 individuals, served as controls.

By comparing these groups, the researchers zeroed in on loci linked to thinness. The top five genomic loci included two intergenic and three intronic loci, including one in ALK. 

In Drosophila, the researchers knocked down the orthologs of two dozen human genes found within 1 Mb of the top five genomic loci linked to thinness. Knocking down five of those genes, a set that included ALK, affected triglyceride levels.

At the same time, ALK knockout mice were thin when fed a standard diet. They ate the same amount and had similar activity levels as the other mice, though they had elevated adiponectin levels and improved glucose homeostasis.

When given a high-fat diet for 16 weeks, the knockout mice gained less weight as compared to wildtype mice on the same diet. Even on this high-fat diet, the knockout mice had normal lean mass, reduced adiposity, and improved glucose tolerance. They did have an elevated daily energy expenditure, the researchers noted, suggesting that this plays a role in protecting them from diet-induced obesity. 

Though ALK is a member of the insulin receptor superfamily, it is largely known for being mutated in a number of cancers. In mice, the researchers noted that ALK is expressed in the cerebellum, cortex, and hypothalamus, but not in other key metabolic tissues such as the liver, muscle, white adipose tissue, and brown adipose tissue. In humans, they noted it is likewise highly expressed in the hypothalamus, and particularly in excitatory neurons.

The thinness-associated loci appear to fall in a region with enhancer activity, and those ALK variants appear to affect ALK expression in various brain tissues. The researchers suggested that ALK expression in neurons of the hypothalamus controls energy expenditure by affecting adipose tissue lipolysis.

There are already drugs that inhibit ALK, the researchers noted. "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," Penninger added. "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."