ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Cell. 2020. doi: 10.1016/j.cell.2020.04.034

Short summary: In this study, rather than focusing on genes associated with obesity, the authors studied genetic variants associated with thinness (BMI <6th percentile for age). In a genome-wide association study from the Estonian Biobank, 881 people were classified as thin, and 3173 individuals with normal weight (BMI 30–50th percentile) served as controls. Five genomic loci (2 intergenic and 3 intronic loci) were identified as associated with thinness, among them the ALK gene.

Comment: The ALK locus has been found to be associated with multiple metabolic traits including BMI, plasma triglyceride levels, plasma LDL-C levels, glucose homeostasis, plasma adiponectin levels and HbA1c. Knockdown of the ALK gene in Drosophila results in reduced triglyceride levels, on normal as well as high-sucrose diets, and exhibited a mild reduction in lifespan, ALK knockout mice were born with normal weight. They developed a thin phenotype at age 5 weeks, which persisted into adulthood. Their body adiposity was reduced and their length was normal. Mice on a standard chow diet exhibited a thin phenotype, elevated adiponectin levels and improved glucose homeostasis, while having unaltered food intake and activity. On challenging adult mice with a high fat diet for 16 weeks, ALK knockout mice were significantly protected against obesity. ALK knockout mice have an elevated daily energy expenditure compared to wildtype mice, suggesting excess catabolism as the potential cause of their adiposity-resistant phenotype.

ALK is a member of the insulin receptor superfamily that was first described as an oncogene. Based on the expression of its mRNA throughout the nervous system during embryogenesis and also in the adult brain, mammalian ALK is thought to play a role in the development and function of the nervous system. ALK is not expressed in the liver, muscle, white adipose tissue and brown adipose tissue.

The researchers suggested that ALK expression in neurons of the hypothalamus regulates energy expenditure by affecting adipose tissue lipolysis.

So now we need ALK inhibitors to be skinny.