Journal
CELL
Volume 181, Issue 6, Pages 1246-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.04.034
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Funding
- Estonian Research Council [IUT20-60]
- European Union Horizon 2020 [692145]
- European Union through the European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED]
- Natural Science Foundation of Guangdong Province [2018B030306002]
- Natural Science Foundation of China [31800993]
- Austrian Science Fund (FWF) [DOC 33-B27]
- Swedish Research Council (Vetenskapsraodet) [2013-3080, 201802838]
- Swedish Brain Foundation (Hjarnfonden) [FO2017-0293, FO2019-0277]
- European Research Council (SECRET-CELLS) [2015-AdG-695136]
- European Community's Seventh Framework Programme (FP/2007-2013)/ERC grant [311701]
- Research Institute of Molecular Pathology (IMP)
- Boehringer Ingelheim
- Austrian Research Promotion Agency (FFG)
- IMBA
- Austrian Academy of Sciences
- T. von Zastrow Foundation
- FWF Wittgenstein award [Z 271-B19]
- Canadian government [C150]
- Austrian Science Fund (FWF) [P27391] Funding Source: Austrian Science Fund (FWF)
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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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