Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity.
Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity.
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在脂肪组织中异位表达活性 TLR4 的转基因小鼠并未表现出胰岛素敏感性受损。
DOI：
10.1002/iid3.162
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hwang,DanielH
中科院分区：
文献类型：
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作者：
Ono-Moore,KikumiD;Zhao,Ling;Huang,Shurong;Kim,Jeonga;Rutkowsky,JenniferM;Snodgrass,RyanG;Schneider,DinaA;Quon,MichaelJ;Graham,JamesL;Havel,PeterJ;Hwang,DanielH
前言慢性低度炎症与肥胖和糖尿病有关。然而，在代谢紊乱中，是什么引起和介导了慢性炎症还不是很清楚。Toll样受体4(TLR4)通过识别病原体相关的分子模式和内源性分子，分别介导感染诱导的炎症和无菌炎症。饱和脂肪酸可激活TLR4，TLR4基因缺陷小鼠可抵抗高脂饮食(HFD)诱导的肥胖和胰岛素抵抗，提示TLR4介导的炎症可能导致代谢功能障碍，如肥胖和胰岛素抵抗。方法我们建立了两个转基因(TG)小鼠，在脂肪组织中表达具有结构性活性的TLR4，并确定这些转基因小鼠是否会表现出更高的胰岛素抵抗。此外，与野生型相比，喂食正常食物的一只TG系母鼠的胰岛素敏感性有所提高，肥胖和体重都有所减少。雌性和雄性小鼠在促炎基因和TLR4信号负调控因子的代谢生物标志物和mRNA表达方面存在显著差异，而不受基因型和饮食的影响。结论TLR4诱导的白色脂肪组织中固有活性的炎症不足以诱导全身性胰岛素抵抗，高脂饮食诱导的胰岛素抵抗可能需要除TLR4介导的炎症外的其他信号。
IntroductionChronic low‐grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll‐like receptor 4 (TLR4) mediates both infection‐induced and sterile inflammation by recognizing pathogen‐associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4‐deficient mice were protected from high fat diet (HFD)‐induced obesity and insulin resistance, suggesting that TLR4‐mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.MethodsWe generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.ResultsTG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild‐type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild‐type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.ConclusionsTogether, these results suggest that constitutively active TLR4‐induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet‐induced insulin resistance may require other signals in addition to TLR4‐mediated inflammation.