Human obesity: FTO, IRX3, or both?
Human obesity: FTO, IRX3, or both?
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DOI：
10.1016/j.molmet.2014.05.003
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发表时间：
2014-08
影响因子：
8.1
通讯作者：
Benedict C
中科院分区：
文献类型：
--
作者：
Cedernaes J;Benedict C
直到最近，在携带肥胖易感基因变异的人中，还缺乏脂肪量和肥胖（FTO）基因表达增强的证据。通过使用来自欧洲血统个体的153个小脑样本的数据集，Smeo和同事现已证明，FTO基因中常见单核苷酸多态性的携带者在小脑中表现出同源盒基因IRX 3的更高表达[1]。他们进一步证明，FTO中与肥胖相关的非编码序列在功能上与IRX 3以兆碱基距离连接。相反，在这项小脑样本的研究中，FTO基因表达在FTO基因型之间没有差异。其他遗传实验显示，整体Irx 3缺陷导致小鼠体重减轻30%[1]。乍一看，这些发现反对增加的中枢神经系统FTO表达对FTO内常见肥胖易感单核苷酸多态性（SNP）携带者中肥胖的贡献，如先前由遗传动物研究的发现所建议的（系统地综述于Ref. [2]）。相反，这些结果表明，IRX 3作为FTO内肥胖相关变体的功能性长期靶点的过表达可能会导致FTO基因中常见单核苷酸多态性携带者的体重增加以及超重和肥胖的发展。然而，一些重要的问题需要更详细的讨论。应该记住的是，所研究的大脑区域小脑并不主要参与食物摄入或食欲调节。然而，脑干和下丘脑肯定是这种情况，正是在后一个区域，Smo和同事发现Irx 3表达对该基因调节的代谢参数起作用[1]。然而，Fto也在下丘脑及其弓状核、室旁核、背内侧核和腹内侧核中高度表达[3]，所有这些都被认为比小脑更高度地参与食欲和能量代谢的调节。可能的是，人中FTO表达在例如下丘脑的这些区域和/或脑干区域中，其中FTO表达在动物模型中进一步显示与进食条件和能量消耗的调节有关（系统综述于参考文献104）。[2])e可以根据FTO基因型进行差异调节。这些数据表明，Fto表达的功能可能以位点依赖性方式发挥作用，因为Fto的整体过表达已显示可引起摄食过多[4]。然而，其他研究表明，至少在小鼠中，Fto蛋白和基因在大脑中的表达在小脑和下丘脑中是均匀的，并且不受短期禁食的影响[5]。在此背景下，需要进一步的研究，其中使用覆盖小脑外脑区域的人脑样本，例如涉及食物摄入抑制控制的前额叶脑区域[6]，直到可以得出关于FTO基因表达与FTO多态性相关的作用的结论。在人类中，依赖于FTO基因型的动态表型也得到了使用功能性磁共振成像（fMRI）的研究的支持。例如，在一项利用fMRI检查葡萄糖摄入后大脑反应的健康参与者研究中，Heni及其同事发现前额叶皮层[7]存在显著的FTO基因型依赖性差异，这是一个高度参与抑制控制的大脑区域，包括食物摄入[6]。此外，另一项fMRI研究发现，...
Until recently, evidence was lacking for an enhanced gene expression of the fat mass and obesity (FTO) gene in humans who carry obesitysusceptible genetic variants in FTO. By using a data set of 153 cerebellar brain samples from individuals of European ancestry, Smemo and colleagues have now demonstrated that carriers of common single nucleotide polymorphisms in the FTO gene exhibit a higher cerebellar expression of the homeobox gene IRX3 [1]. They further demonstrated that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with IRX3. In contrast, in this study of cerebellar samples, FTO gene expression did not differ between FTO genotypes. Additional genetic experiments revealed that global Irx3 deficiency led to a w30% body weight reduction in mice [1]. At first glance, these findings argue against a contribution of increased central nervous system FTO expression to obesity in carriers of common obesity susceptible single nucleotide polymorphisms (SNPs) within FTO, as previously suggested by findings from genetic animal studies (systematically reviewed in Ref.[2]). Instead, these results suggest that overexpression of IRX3 as a functional long-range target of obesityassociated variants within FTO might drive weight gain and the development of overweight and obesity in carriers of common single nucleotide polymorphisms in the FTO gene. However, some important points require more detailed discussion. It should be borne in mind that the studied brain region e the cerebellum e is not primarily involved in food intake or appetite regulation. This is however certainly the case for the brainstem and the hypothalamus, and it was in this latter region that Smemo and colleagues found Irx3 expression to play a role for the metabolic parameters regulated by this gene [1]. Fto is however also highly expressed in especially the hypothalamus and its arcuate, paraventricular, dorsomedial and ventromedial nuclei [3], all of which are recognized to be much more highly involved in the regulation of appetite and energy metabolism than the cerebellum. It is possible that FTO expression in humans in eg these regions of the hypothalamus, and/or brainstem e regions in which Fto expression in animal models furthermore has been shown to be implicated in feeding condition and regulation of energy expenditure (systematically reviewed in Ref.[2]) e could be differentially regulated depending on FTO genotype. These data suggest that the function of Fto expression may function in a site dependently manner, as global overexpression of Fto has been shown to cause hyperphagia [4]. Other studies however suggest that Fto protein and gene expression in the brain at least in mice is uniform across eg the cerebellum and hypothalamus e furthermore being unaffected by short-term fasting [5]. Against this background, further studies are needed where human brain samples covering extracerebellar brain regions are utilized e eg prefrontal brain regions involved in the inhibitory control of food intake [6] e until the conclusion can be drawn as to the role of the FTO gene expression in relation to FTO polymorphisms.Interestingly, a dynamic phenotype depending on FTO genotype is also supported in humans by studies using functional magnetic resonance imaging (fMRI). For instance, in a study of healthy participants utilizing fMRI to examine the brain response post-glucose ingestion, Heni and colleagues found significant FTO-genotype dependent differences in the prefrontal cortex [7], a brain region highly involved in inhibitory control, comprising that on food intake [6]. Moreover, another fMRI study found that …
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
McTaggart JS;Lee S;Iberl M;Church C;Cox RD;Ashcroft FM
通讯作者：
Ashcroft FM
影响因子：
64.8
作者：
Smemo, Scott;Tena, Juan J.;Kim, Kyoung-Han;Gamazon, Eric R.;Sakabe, Noboru J.;Gomez-Marin, Carlos;Aneas, Ivy;Credidio, Flavia L.;Sobreira, Debora R.;Wasserman, Nora F.;Lee, Ju Hee;Puviindran, Vijitha;Tam, Davis;Shen, Michael;Son, Joe Eun;Vakili, Niki Alizadeh;Sung, Hoon-Ki;Naranjo, Silvia;Acemel, Rafael D.;Manzanares, Miguel;Nagy, Andras;Cox, Nancy J.;Hui, Chi-Chung;Luis Gomez-Skarmeta, Jose;Nobrega, Marcelo A.
通讯作者：
Nobrega, Marcelo A.
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
8.1
作者：
Heni, Martin;Kullmann, Stephanie;Fritsche, Andreas
通讯作者：
Fritsche, Andreas