MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom.
PLoS Genet. 2013;9(1):e1003166. doi: 10.1371/journal.pgen.1003166. Epub 2013 Jan 3.
The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.
在人类中，与 BMI 关联最强的 GWAS 基因座是 FTO 基因。啮齿动物研究表明 FTO 在能量平衡和身体成分中起作用。表达缺失研究中观察到的表型是复杂的，包括围产期致死、断奶后生长迟缓以及身体成分的显著改变。因此，了解 FTO 如何以及在何处调节食物摄入、能量消耗和身体成分是一个挑战。为了解决这个问题，我们生成了一系列具有不同时空 Fto 表达缺失的小鼠。Fto 基因的种系缺失导致高围产期致死率和体长、脂肪量和瘦体重减少。当按瘦体重比例校正时，小鼠的能量消耗显著增加，但更适当的多元线性回归正常化显示能量消耗没有差异。在子宫内和围产期后（6 周龄），全球缺失 Fto 消除了种系缺失的高致死率。然而，9 周时体重减轻，主要是瘦体重减少。在随后的 10 周内，体重趋同，这是由脂肪量增加驱动的。随着呼吸商的降低，出现了一种转变，但总体食物摄入量或能量消耗没有变化。为了测试表型是否可以通过中脑基底下丘脑的 Fto 缺失来解释，我们立体定向注射编码 Cre 重组酶的腺相关病毒载体以引起区域缺失。我们观察到食物摄入量和体重增加减少，但对能量消耗或身体成分没有影响。因此，尽管下丘脑 Fto 可以影响摄食，但 Fto 对身体成分的影响是由其在其他部位的作用引起的。我们的数据表明，Fto 可能在控制瘦体重方面具有关键作用，独立于其对食物摄入的影响。
