1. Identification of ALK in Thinness.
- Author
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Orthofer M, Valsesia A, Mägi R, Wang QP, Kaczanowska J, Kozieradzki I, Leopoldi A, Cikes D, Zopf LM, Tretiakov EO, Demetz E, Hilbe R, Boehm A, Ticevic M, Nõukas M, Jais A, Spirk K, Clark T, Amann S, Lepamets M, Neumayr C, Arnold C, Dou Z, Kuhn V, Novatchkova M, Cronin SJF, Tietge UJF, Müller S, Pospisilik JA, Nagy V, Hui CC, Lazovic J, Esterbauer H, Hagelkruys A, Tancevski I, Kiefer FW, Harkany T, Haubensak W, Neely GG, Metspalu A, Hager J, Gheldof N, and Penninger JM
- Subjects
- Adipose Tissue metabolism, Adult, Animals, Cell Line, Cohort Studies, Drosophila genetics, Estonia, Female, Humans, Leptin genetics, Lipolysis genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity genetics, RNA Interference physiology, Young Adult, Anaplastic Lymphoma Kinase genetics, Thinness genetics
- 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 6
th 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., Competing Interests: Declaration of Interests J.H., N.G., and A.V. are employed by Nestlé Research. J.H., N.G., and A.V. have filed a patent on Methods of Modulating ALK (WO2019101490)., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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