FTO is necessary for the induction of leptin resistance by high-fat feeding.
FTO is necessary for the induction of leptin resistance by high-fat feeding.
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FTO对于通过高脂喂养诱导瘦素耐药性是必需的。
DOI：
10.1016/j.molmet.2015.01.011
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发表时间：
2015-04
影响因子：
8.1
通讯作者：
Yeo GS
中科院分区：
文献类型：
--
作者：
Tung YC;Gulati P;Liu CH;Rimmington D;Dennis R;Ma M;Saudek V;O'Rahilly S;Coll AP;Yeo GS
功能缺失的FTO突变显著影响人类和小鼠的身体组成，据报道，FTO缺陷小鼠对高脂饮食(HFD)的反应是抵抗肥胖的发展。我们的目的是进一步探讨FTO与HFD之间的相互作用，并确定FTO是否会影响HFD的不良代谢后果。我们研究了两种有效的瘦素抵抗模型(HFD喂养和中央棕榈酸酯注射)中FTO缺乏的小鼠，以确定FTO基因可能如何影响瘦素的作用。通过对下丘脑组织的转录分析来确定FTO丢失影响的相关途径，我们结合免疫共沉淀、酵母双杂交和荧光素酶报告实验的数据来确定FTO影响瘦素抵抗状态发展的机制。FTO缺乏的小鼠对HFD的反应显著增加了它们的脂肪质量。FTO+/−和FTO−/−小鼠仍然对瘦素的厌食效应敏感，无论是在暴露于高脂饮食后，还是在急性中枢应用棕榈酸酯之后。在肾衰后，FTO缺陷小鼠的下丘脑中，编码NF-кB信号通路成分的基因下调。当FTO缺乏的小鼠使用单一低中心剂量的肿瘤坏死因子α重新激活这一途径时，小鼠对瘦素的影响变得不那么敏感。我们发现转录辅助激活因子TRIP4是FTO的结合伙伴，也是依赖TRIP4反式激活NFкB所必需的分子。我们的研究表明，FTO通过改变下丘脑NFкB信号来影响HFD的代谢结果，而不依赖于体重。这支持了FTO活性的药理调节可能在改善瘦素敏感性方面具有潜在的治疗益处的观点，其方式受营养环境的影响。
Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD. We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co-immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states. Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto+/− and Fto−/− mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFкB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFα, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFкB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFкB. Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFкB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.5
作者：
Heard-Costa NL;Zillikens MC;Monda KL;Johansson A;Harris TB;Fu M;Haritunians T;Feitosa MF;Aspelund T;Eiriksdottir G;Garcia M;Launer LJ;Smith AV;Mitchell BD;McArdle PF;Shuldiner AR;Bielinski SJ;Boerwinkle E;Brancati F;Demerath EW;Pankow JS;Arnold AM;Chen YD;Glazer NL;McKnight B;Psaty BM;Rotter JI;Amin N;Campbell H;Gyllensten U;Pattaro C;Pramstaller PP;Rudan I;Struchalin M;Vitart V;Gao X;Kraja A;Province MA;Zhang Q;Atwood LD;Dupuis J;Hirschhorn JN;Jaquish CE;O'Donnell CJ;Vasan RS;White CC;Aulchenko YS;Estrada K;Hofman A;Rivadeneira F;Uitterlinden AG;Witteman JC;Oostra BA;Kaplan RC;Gudnason V;O'Connell JR;Borecki IB;van Duijn CM;Cupples LA;Fox CS;North KE
通讯作者：
North KE
影响因子：
15.9
作者：
Berglund, Eric D.;Vianna, Claudia R.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
通过小鼠和人 FTO 对单链 DNA 和 RNA 中的 3-甲基胸腺嘧啶和 3-甲基尿嘧啶进行氧化去甲基化。
影响因子：
3.5
作者：
Jia, Guifang;Yang, Cai-Guang;Yang, Shangdong;Jian, Xing;Yi, Chengqi;Zhou, Zhiqiang;He, Chuan
通讯作者：
He, Chuan
影响因子：
8.1
作者：
Cedernaes J;Benedict C
通讯作者：
Benedict C