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Identification of ALK in Thinness.
Cell ( IF 64.5 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.cell.2020.04.034
Michael Orthofer 1 , Armand Valsesia 2 , Reedik Mägi 3 , Qiao-Ping Wang 4 , Joanna Kaczanowska 5 , Ivona Kozieradzki 1 , Alexandra Leopoldi 1 , Domagoj Cikes 1 , Lydia M Zopf 6 , Evgenii O Tretiakov 7 , Egon Demetz 8 , Richard Hilbe 8 , Anna Boehm 8 , Melita Ticevic 1 , Margit Nõukas 3 , Alexander Jais 9 , Katrin Spirk 10 , Teleri Clark 11 , Sabine Amann 9 , Maarja Lepamets 3 , Christoph Neumayr 5 , Cosmas Arnold 5 , Zhengchao Dou 12 , Volker Kuhn 8 , Maria Novatchkova 5 , Shane J F Cronin 1 , Uwe J F Tietge 13 , Simone Müller 14 , J Andrew Pospisilik 15 , Vanja Nagy 16 , Chi-Chung Hui 12 , Jelena Lazovic 6 , Harald Esterbauer 9 , Astrid Hagelkruys 1 , Ivan Tancevski 8 , Florian W Kiefer 10 , Tibor Harkany 17 , Wulf Haubensak 5 , G Gregory Neely 11 , Andres Metspalu 3 , Jorg Hager 2 , Nele Gheldof 2 , Josef M Penninger 18
Affiliation  

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.



中文翻译:

ALK 的稀度鉴定。

尽管世界大部分地区的肥胖环境相同,但体重增加的易感性存在相当大的个体差异。尽管许多研究都集中在确定肥胖的遗传易感性上,但我们对一个独特表型的爱沙尼亚队列中代谢健康的瘦人(整个人群 BMI 谱中最低的第 6个百分位数)进行了 GWAS。我们发现间变性淋巴瘤激酶 ( ALK ) 作为候选瘦弱基因。在果蝇中,RNAi 介导的Alk敲低导致甘油三酯水平降低。在小鼠中, Alk基因缺失导致瘦弱的动物对饮食和瘦素突变引起的肥胖具有显着的抵抗力。从机制上讲,我们发现下丘脑神经元中的 ALK 表达通过交感神经控制脂肪组织脂解来控制能量消耗。我们的遗传和机制实验将ALK确定为一种瘦身基因,它与抵抗体重增加有关。

更新日期:2020-05-21
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