Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice.
Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice.
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DOI：
10.1007/s00125-017-4341-0
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发表时间：
2017-10
期刊：
影响因子：
8.2
通讯作者：
Holmberg D
中科院分区：
文献类型：
--
作者：
Hannibal TD;Schmidt-Christensen A;Nilsson J;Fransén-Pettersson N;Hansen L;Holmberg D
肥胖与葡萄糖耐受不良和胰岛素抵抗有关，并与2型糖尿病的日益流行密切相关。在饮食性肥胖（DIO）和2型糖尿病小鼠模型中，脂肪摄入增加导致脂肪组织扩张和促炎细胞因子的分泌。先天免疫系统不仅在肥胖相关的慢性低度炎症中起着至关重要的作用，而且还被认为在调节能量代谢中发挥作用。然而，在饮食摄入增加的早期阶段，免疫系统对新陈代谢的调节如何促进肥胖的增加，我们知之甚少。在这里，我们旨在确定I型ifn在DIO和胰岛素抵抗中的作用。缺乏IFN-α受体（IFNAR - / -）和缺乏浆细胞样树突状细胞（pDCs） （B6.E2-2fl/fl.Itgax-cre）的小鼠喂食高脂肪饲料或正常饲料。采用细胞、生化和分子方法对小鼠进行体内和体外分析。我们发现，无法对I型ifn作出反应抑制了肥胖的发展。此外，该模型中肥胖和胰岛素抵抗的发展与肥胖小鼠脂肪组织和肝脏的pDC募集有关（分别增加4.3倍和2.7倍）。最后，我们证明了pDCs的消耗可以保护小鼠免受DIO和肥胖相关的代谢并发症。我们的研究结果为pDCs通过I型ifn调节能量代谢并促进肥胖的发生提供了遗传学证据。
Obesity is associated with glucose intolerance and insulin resistance and is closely linked to the increasing prevalence of type 2 diabetes. In mouse models of diet-induced obesity (DIO) and type 2 diabetes, an increased fat intake results in adipose tissue expansion and the secretion of proinflammatory cytokines. The innate immune system not only plays a crucial role in obesity-associated chronic low-grade inflammation but it is also proposed to play a role in modulating energy metabolism. However, little is known about how the modulation of metabolism by the immune system may promote increased adiposity in the early stages of increased dietary intake. Here we aimed to define the role of type I IFNs in DIO and insulin resistance. Mice lacking the receptor for IFN-α (IFNAR−/−) and deficient in plasmacytoid dendritic cells (pDCs) (B6.E2-2fl/fl.Itgax-cre) were fed a diet with a high fat content or normal chow. The mice were analysed in vivo and in vitro using cellular, biochemical and molecular approaches. We found that the development of obesity was inhibited by an inability to respond to type I IFNs. Furthermore, the development of obesity and insulin resistance in this model was associated with pDC recruitment to the fatty tissues and liver of obese mice (a 4.3-fold and 2.7-fold increase, respectively). Finally, we demonstrated that the depletion of pDCs protects mice from DIO and from developing obesity-associated metabolic complications. Our results provide genetic evidence that pDCs, via type I IFNs, regulate energy metabolism and promote the development of obesity.
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影响因子：
16.2
作者：
Ghanim H;Abuaysheh S;Sia CL;Korzeniewski K;Chaudhuri A;Fernandez-Real JM;Dandona P
通讯作者：
Dandona P
影响因子：
6.7
作者：
Lazear HM;Lancaster A;Wilkins C;Suthar MS;Huang A;Vick SC;Clepper L;Thackray L;Brassil MM;Virgin HW;Nikolich-Zugich J;Moses AV;Gale M Jr;Früh K;Diamond MS
通讯作者：
Diamond MS
影响因子：
15.9
作者：
Garcia-Martinez, Irma;Santoro, Nicola;Mehal, Wajahat Zafar
通讯作者：
Mehal, Wajahat Zafar
影响因子：
3.5
作者：
Pattison MJ;MacKenzie KF;Elcombe SE;Arthur JS
通讯作者：
Arthur JS
影响因子：
5.6
作者：
Kim, Seung-Jin;Choi, Youngshim;Park, Taesun
通讯作者：
Park, Taesun