Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice
Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice
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巨噬细胞 mTORC1 破坏可减少肥胖小鼠的炎症和胰岛素抵抗
DOI：
10.1007/s00125-014-3350-5
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发表时间：
2014-11-01
期刊：
影响因子：
8.2
通讯作者：
Ai, Ding
中科院分区：
文献类型：
--
作者：
Jiang, Hongfeng;Westerterp, Marit;Ai, Ding
目的/假设巨噬细胞分泌的炎症因子在肥胖相关的胰岛素抵抗中起重要作用。哺乳动物靶标雷帕霉素复合体1(MTORC1)处于营养激素信号网络的十字路口，在调节能量平衡和外周新陈代谢中发挥重要作用。然而，巨噬细胞mTORC1在胰岛素抵抗中的作用仍不清楚。在本研究中，我们研究了巨噬细胞mTORC1在调节炎症和胰岛素敏感性中的生理作用。方法通过将巨噬细胞中mTOR调节相关蛋白(Raptor)调节相关蛋白(Raptor)缺失的小鼠与Lysm-Cre启动子(Mac-Raptor(KO))控制下表达Cre重组酶的小鼠(Raptor(FLOX/FLOX))杂交，获得了巨噬细胞mTOR调节相关蛋白(Raptor)缺陷的小鼠。我们给小鼠喂食食物或高脂饮食(HFD)，并评估肝脏、肌肉和脂肪组织中的胰岛素敏感性。随后，我们检测了肝脏和脂肪组织中炎症基因的表达，并研究了Raptor缺陷在HFD喂养的小鼠腹膜巨噬细胞或棕榈酸刺激的骨髓来源巨噬细胞(BMDM)炎症反应中的调节作用。结果与Raptor(FLOX/FLOX)小鼠相比，喂养HFD的Mac-RaptorKO小鼠全身胰岛素敏感性得到改善。巨噬细胞Raptor缺乏可降低HFD大鼠肝脏和脂肪组织中炎症基因的表达、脂肪肝和脂肪组织中巨噬细胞的含量。在饲喂HFD 12周的小鼠的腹膜巨噬细胞中，巨噬细胞Raptor缺乏通过减弱Akt的失活和随后抑制肌醇需要元件1α/Clun NH2末端激酶-核因子kappa-轻链-激活的B细胞的轻链增强器(IRE1α/JNK/NF kappa B)通路来减少炎症基因的表达。同样，Raptor缺乏或雷帕霉素治疗导致的mTOR抑制减少了棕榈酸诱导的BMDM中炎症基因的表达。结论/解释巨噬细胞中mTORC1信号的中断可能通过抑制HFD和棕榈酸诱导的IRE1α/JNK/NF kappa B途径的激活来保护小鼠免受炎症和胰岛素抵抗。
Aims/hypothesis Inflammatory factors secreted by macrophages play an important role in obesity-related insulin resistance. Being at the crossroads of a nutrient-hormonal signalling network, the mammalian target of rapamycin complex 1 (mTORC1) controls important functions in the regulation of energy balance and peripheral metabolism. However, the role of macrophage mTORC1 in insulin resistance is still unclear. In the current study, we investigated the physiological role of macrophage mTORC1 in regulating inflammation and insulin sensitivity.Methods We generated mice deficient in the regulatory associated protein of mTOR (Raptor) in macrophages, by crossing Raptor (also known as Rptor) floxed mice (Raptor(flox/flox)) with mice expressing Cre recombinase under the control of the Lysm-Cre promoter (Mac-Raptor(KO)). We fed mice chow or high-fat diet (HFD) and assessed insulin sensitivity in liver, muscle and adipose tissue. Subsequently, we measured inflammatory gene expression in liver and adipose tissue and investigated the role of Raptor deficiency in the regulation of inflammatory responses in peritoneal macrophages from HFD-fed mice or in palmitic acid-stimulated bone marrow-derived macrophages (BMDMs).Results Mac-RaptorKO mice fed HFD had improved systemic insulin sensitivity compared with Raptor(flox/flox) mice. Macrophage Raptor deficiency reduced inflammatory gene expression in liver and adipose tissue, fatty liver and adipose tissue macrophage content in response to HFD. In peritoneal macrophages from mice fed with an HFD for 12 weeks, macrophage Raptor deficiency decreased inflammatory gene expression, through attenuation of the inactivation of Akt and subsequent inhibition of the inositol-requiring element 1 alpha/clun NH2-terminal kinase-nuclear factor kappa-lightchain-enhancer of activated B cells (IRE1 alpha/JNK/NF kappa B) pathways. Similarly, mTOR inhibition as a result of Raptor deficiency or rapamycin treatment decreased palmitic acid-induced inflammatory gene expression in BMDMs in vitro.Conclusions/interpretation The disruption of mTORC1 signalling in macrophages protects mice against inflammation and insulin resistance potentially by inhibiting HFD- and palmitic acid-induced IRE1 alpha/JNK/NF kappa B pathway activation.