Identification of ALK in Thinness
Authors: Jorg Hager
Teleri Clark
Harald Esterbauer
Anna Boehm
G Gregory Neely
Chi-Chung Hui
Wulf Haubensak
Simone Müller
Andres Metspalu
Alexandra Leopoldi
Nele Gheldof
Uwe J F Tietge
Cosmas Arnold
Armand Valsesia
Melita Ticevic
Michael Orthofer
Evgenii O Tretiakov
Lydia M Zopf
Reedik Mägi
Josef M Penninger
Alexander Jais
Katrin Spirk
Richard Hilbe
Ivan Tancevski
Tibor Harkany
Astrid Hagelkruys
Domagoj Cikes
Ivona Kozieradzki
Margit Nõukas
Joanna Kaczanowska
Maria Novatchkova
Egon Demetz
Sabine Amann
Florian W Kiefer
Jelena Lazovic
Zhengchao Dou
Shane J F Cronin
Vanja Nagy
Christoph Neumayr
Qiao-Ping Wang
J Andrew Pospisilik
Volker Kuhn
Maarja Lepamets
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: GWAS; anaplastic lymphoma kinase; energy expenditure; hypothalamus; lipolysis
Affiliations: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria., Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland., Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia., School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China., IMP, Institute of Molecular Pathology, Vienna 1030, Austria., Vienna BioCenter Core Facilities GmbH (VBCF), Vienna 1030, Austria., 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., Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland. Electronic address: ., 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: .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Why is a different gal4 driver used for the experiments in overexpression of ALK compared with knockdown? Also it seems Gal80ts was used (Figure S2). What is the rationale for the different system, is the expression and efficiency identical? Can the authors show that they are equally efficient? Ideally the article should include methods for the Gal80 use. , 
 No rationale for the arbitrary selection of BMI percentiles in the GWAS analysis. p-value for ALK 1.4E-06 not really convincing of any genetic effect in humans ,