Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria.
Department of Internal Medicine II, Innsbruck Medical University, Innsbruck 6020, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna 1090, Austria.
Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 141 52 Huddinge, Sweden; Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, 141 86 Stockholm, Sweden.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria.
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria; Section for Chemical Neurotransmission, Department of Neuroscience, Biomedicum 7D, Solnavägen 9, 17165 Solna, Sweden.
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: josef.penninger@ubc.ca.
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.
