Fischer Julia, Koch Linda, Emmerling Christian, Vierkotten Jeanette, Peters Thomas, Brüning Jens C, Rüther Ulrich
Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
Nature. 2009 Apr 16;458(7240):894-8. doi: 10.1038/nature07848. Epub 2009 Feb 22.
Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
多项独立的全基因组关联研究已确定，人体体重指数与FTO基因多态性之间存在很强的相关性。第一个内含子中的常见变异定义了一个易导致肥胖的风险等位基因，该风险等位基因的纯合子比低风险等位基因的纯合子体重约重3千克。然而，FTO在能量稳态中的功能作用仍不清楚。我们在此表明，小鼠中Fto的缺失会导致出生后生长迟缓，脂肪组织和瘦体重显著减少。尽管Fto基因缺陷小鼠的自发运动活动减少且相对食量增加，但由于能量消耗增加和全身交感神经激活，它们仍会变瘦。综上所述，据我们所知，这些实验首次直接证明Fto通过控制能量消耗在功能上参与能量稳态。
