Identification of ALK in Thinness

• Published in: Cell Vol. 181; no. 6; pp. 1246 - 1262.e22
• Main Authors: Orthofer, Michael, Valsesia, Armand, Mägi, Reedik, Wang, Qiao-Ping, Kaczanowska, Joanna, Kozieradzki, Ivona, Leopoldi, Alexandra, Cikes, Domagoj, Zopf, Lydia M., Tretiakov, Evgenii O., Demetz, Egon, Hilbe, Richard, Boehm, Anna, Ticevic, Melita, Nõukas, Margit, Jais, Alexander, Spirk, Katrin, Clark, Teleri, Amann, Sabine, Lepamets, Maarja, Neumayr, Christoph, Arnold, Cosmas, Dou, Zhengchao, Kuhn, Volker, Novatchkova, Maria, Cronin, Shane J.F., Tietge, Uwe J.F., Müller, Simone, Pospisilik, J. Andrew, Nagy, Vanja, Hui, Chi-Chung, Lazovic, Jelena, Esterbauer, Harald, Hagelkruys, Astrid, Tancevski, Ivan, Kiefer, Florian W., Harkany, Tibor, Haubensak, Wulf, Neely, G. Gregory, Metspalu, Andres, Hager, Jorg, Gheldof, Nele, Penninger, Josef M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-06-2020
• Subjects: Adipose Tissue - metabolism; Adult; anaplastic lymphoma kinase; Anaplastic Lymphoma Kinase - genetics; Animals; Cell Line; Cohort Studies; Drosophila - genetics; energy expenditure; Estonia; Female; GWAS; Humans; hypothalamus; Leptin - genetics; lipolysis; Lipolysis - genetics; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; norepinephrine; Obesity - genetics; RNA Interference - physiology; thinness; Thinness - genetics; Young Adult; Estonia; norepinephrine; GWAS; anaplastic lymphoma kinase; energy expenditure; lipolysis; thinness; hypothalamus
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.04.034

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.
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•GWAS in the EGCUT biobank identifies ALK as a candidate thinness gene•Knockdown of Alk in Drosophila results in reduced triglyceride levels•Alk mutant mice exhibit resistance to diet- and leptin-mutation-induced obesity•ALK controls energy expenditure via sympathetic tone to the adipose organ
Genetic association studies in an Estonian biobank implicate ALK in the regulation of thinness. Studies in Drosophila and mice show that ALK functions as a regulator of sympathetic tone and loss of ALK leads to resistance to weight gain.