Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance.
Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance.
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作者：
Lee YS;Li P;Huh JY;Hwang IJ;Lu M;Kim JI;Ham M;Talukdar S;Chen A;Lu WJ;Bandyopadhyay GK;Schwendener R;Olefsky J;Kim JB
组织炎症是导致既往肥胖患者胰岛素抵抗的关键因素。几种免疫受损的小鼠模型可以防止肥胖引起的胰岛素抵抗。然而，在肥胖症中，炎症是否会引发全身性胰岛素抵抗，或者反之亦然，目前还没有答案。本研究的目的是评估这些问题。我们给野生型小鼠和三种不同的免疫受损小鼠模型(淋巴细胞缺陷的Rag1基因敲除小鼠、巨噬细胞耗竭的小鼠和造血细胞特异性的Jun NH2末端激酶缺陷小鼠)喂饲高脂饮食(HFD)，并测量了巨噬细胞含量、炎症标志物和脂肪组织、肝脏和骨骼肌中脂肪积累以及全身胰岛素敏感性的时间进程。在野生型小鼠中，体重和脂肪组织质量以及胰岛素抵抗在HFD 3天后明显增加。同时，在短期HFD期间，脂肪组织中的炎症被选择性地升高。然而，有趣的是，所有三种免疫受损的小鼠模型都没有受到短期HFD诱导的胰岛素抵抗的保护。另一方面，肝脏和骨骼肌脂类含量在HFD第3天显著增加。这些数据表明，高脂饮食诱导的胰岛素抵抗的初始阶段与炎症无关，而肥胖患者更慢性的胰岛素抵抗状态在很大程度上是由巨噬细胞诱导的促炎作用介导的。HFD喂养过程中出现的早发性胰岛素抵抗更可能与急性组织脂质过载有关。
Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions. We fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase–deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity. In wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD. These data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.