Macrophage migration inhibitory factor deficiency ameliorates high-fat diet induced insulin resistance in mice with reduced adipose inflammation and hepatic steatosis.
Macrophage migration inhibitory factor deficiency ameliorates high-fat diet induced insulin resistance in mice with reduced adipose inflammation and hepatic steatosis.
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DOI：
10.1371/journal.pone.0113369
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Roche HM
中科院分区：
文献类型：
--
作者：
Finucane OM;Reynolds CM;McGillicuddy FC;Harford KA;Morrison M;Baugh J;Roche HM
巨噬细胞浸润是高脂饮食诱导的脂肪组织炎症和胰岛素抵抗的关键决定因素。巨噬细胞募集和激活的确切机制尚不清楚。巨噬细胞移动抑制因子（MIF），一种促炎细胞因子，显示趋化因子样特性。循环中的MIF水平在肥胖期间升高，然而其在高脂饮食诱导的脂肪炎症和胰岛素抵抗中的作用仍然是难以捉摸的。野生型和MIF−/− C57B1\6J小鼠喂食普通饲料或高脂饮食。评估体重和摄食量。通过葡萄糖和胰岛素耐量试验监测葡萄糖稳态。评估脂肪组织巨噬细胞募集和脂肪组织胰岛素敏感性。测量基质血管组分、脂肪外植体和骨髓巨噬细胞的细胞因子分泌。对与野生型和MIF−/−巨噬细胞共培养的3 T3-L1-脂肪细胞的炎症特征和胰岛素敏感性进行定量。评估肝脏甘油三酯水平。MIF−/−表现出体重增加减少。年龄和体重匹配的肥胖MIF−/−小鼠表现出改善的葡萄糖稳态，同时减少脂肪组织M1巨噬细胞浸润。与野生型相比，肥胖MIF−/−基质血管组分分泌较少的TNFα和较多的IL-10。JNK的激活在肥胖的MIF−/−脂肪中受损，伴随着pAKT的表达。与MIF−/−巨噬细胞一起培养的3 T3-L1-脂肪细胞减少了促炎性细胞因子分泌并改善了胰岛素敏感性，这一效果也是通过MIF抑制剂ISO-1获得的。MIF−/−肝脏显示肝甘油三酯蓄积减少、pAKT表达增强和NFκB活化减少。MIF缺乏通过减少巨噬细胞浸润，改善脂肪炎症，从而改善脂肪细胞离体胰岛素抵抗，部分保护高脂饮食诱导的胰岛素抵抗。MIF代表了治疗高脂饮食诱导的胰岛素抵抗的潜在治疗靶点。
Macrophage infiltration is a critical determinant of high-fat diet induced adipose tissue inflammation and insulin resistance. The precise mechanisms underpinning the initiation of macrophage recruitment and activation are unclear. Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, displays chemokine-like properties. Circulating MIF levels are elevated during obesity however its role in high-fat diet induced adipose inflammation and insulin resistance remains elusive. Wildtype and MIF−/− C57Bl\6J mice were fed chow or high-fat diet. Body weight and food intake was assessed. Glucose homeostasis was monitored by glucose and insulin tolerance tests. Adipose tissue macrophage recruitment and adipose tissue insulin sensitivity was evaluated. Cytokine secretion from stromal vascular fraction, adipose explants and bone marrow macrophages was measured. Inflammatory signature and insulin sensitivity of 3T3-L1-adipocytes co-cultured with wildtype and MIF−/− macrophage was quantified. Hepatic triacylglyceride levels were assessed. MIF−/− exhibited reduced weight gain. Age and weight-matched obese MIF−/− mice exhibited improved glucose homeostasis coincident with reduced adipose tissue M1 macrophage infiltration. Obese MIF−/− stromal vascular fraction secreted less TNFα and greater IL-10 compared to wildtype. Activation of JNK was impaired in obese MIF−/−adipose, concomitant with pAKT expression. 3T3-L1-adipocytes cultured with MIF−/− macrophages had reduced pro-inflammatory cytokine secretion and improved insulin sensitivity, effects which were also attained with MIF inhibitor ISO-1. MIF−/− liver exhibited reduced hepatic triacyglyceride accumulation, enhanced pAKT expression and reduced NFκB activation. MIF deficiency partially protects from high-fat diet induced insulin resistance by attenuating macrophage infiltration, ameliorating adipose inflammation, which improved adipocyte insulin resistance ex vivo. MIF represents a potential therapeutic target for treatment of high-fat diet induced insulin resistance.
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影响因子：
7.7
作者：
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作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
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