Identification of ALK in Thinness

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Karolinska University Hospital
Hosp Sick Children
Van Andel Inst
Ludwig Boltzmann Inst Rare & Undiagnosed Dis
University of Tartu
Sun Yat Sen Univ
Vienna BioCenter Core Facilities
Ecole Polytechnique Federale de Lausanne
Universität Sydney
Medizinische Universität Innsbruck
Medizinische Universität Wien - AKH
Institut für Molekulare Biotechnologie GmbH
University of British Columbia
University of Toronto
Research Institute of Molecular Pathology
Veterinärmedizinische Universität Wien
Karolinska Institutet
Van Andel Institute
Biomedicum 7D
Sun Yat Sen University
Swiss Federal Institutes of Technology Domain
University of Sydney