Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
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DOI：
10.1172/jci200319451
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发表时间：
2003-12-01
影响因子：
15.9
通讯作者：
Chen, H
中科院分区：
文献类型：
--
作者：
Xu, HY;Barnes, GT;Chen, H
胰岛素抵抗源于胰岛素在调节外周组织营养代谢方面无法正常发挥作用。来自人群研究和动物研究的越来越多的证据已经确立了慢性炎症和胰岛素抵抗之间的相关性以及因果联系。然而，潜在的分子通路在很大程度上是未知的。在本报告中，我们表明在遗传性和高脂肪饮食诱导的肥胖（DIO）小鼠模型中，白色脂肪组织（WAT）中许多炎症和巨噬细胞特异性基因显著上调。在患有DIO的小鼠的白色脂肪组织中，这种上调逐渐增加，并且先于循环胰岛素水平的显著升高。在用胰岛素增敏药物罗格列酮治疗后，这些源自巨噬细胞的基因被下调。从组织学上看，有证据表明巨噬细胞而非中性粒细胞和淋巴细胞大量浸润到肥胖小鼠的白色脂肪组织中，同时伴有脂肪细胞脂解和多核巨细胞形成的迹象。这些数据表明白色脂肪组织中的巨噬细胞在病态肥胖中起积极作用，并且与巨噬细胞相关的炎症活动可能导致肥胖诱导的胰岛素抵抗的发病机制。我们提出，与肥胖相关的胰岛素抵抗至少在一定程度上是一种在脂肪组织中引发的慢性炎症疾病。
Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.