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Orthofer, M., Valsesia, A., Mägi, R., Wang, Q.P., Kaczanowska, J., Kozieradzki, I., Leopoldi, A., Cikes, D., Zopf, L.M., Tretiakov, E.O., 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, S.J.F., Tietge, U.J.F., Müller, S., Pospisilik, J.A., Nagy, V., Hui, C.C., Lazovic, J., Esterbauer, H., Hagelkruys, A., Tancevski, I., Kiefer, F.W., Harkany, T., Haubensak, W., Neely, G.G., Metspalu, A., Hager, J., Gheldof, N., Penninger, J.M. (2020). Identification of ALK in Thinness.  Cell 181(6): 1246--1262.e22.
FlyBase ID
FBrf0245920
Publication Type
Research paper
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.

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    Language of Publication
    English
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    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell
    Title
    Cell
    Publication Year
    1974-
    ISBN/ISSN
    0092-8674
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