Inflammasome is a central player in the induction of obesity and insulin resistance
Inflammasome is a central player in the induction of obesity and insulin resistance
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DOI：
10.1073/pnas.1100255108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Kanneganti, Thirumala-Devi
中科院分区：
文献类型：
--
作者：
Stienstra, Rinke;van Diepen, Janna A.;Kanneganti, Thirumala-Devi
炎症在肥胖的发病机制中起着关键作用。慢性过度喂养导致脂肪组织中的巨噬细胞浸润，导致促炎细胞因子产生。微生物和内源性危险信号都触发细胞内先天免疫传感器Nlrp 3的组装，导致半胱天冬酶-1活化和促炎细胞因子IL-1 β和IL-18的产生。在这里，我们发现Nlrp 3、肥胖相关斑点样蛋白和caspase-1缺陷的小鼠对高脂饮食诱导的肥胖的发展具有抵抗性，这与保护肥胖诱导的胰岛素抵抗相关。此外，肝脏甘油三酯含量，脂肪细胞的大小，并在脂肪组织中的巨噬细胞浸润都减少在小鼠缺乏炎症体成分。单核细胞趋化蛋白（MCP）-1是介导巨噬细胞浸润的关键分子。事实上，炎性小体活化缺陷与脂肪组织中MCP-1产生减少有关。此外，影响能量利用和胰岛素敏感性的血浆瘦素和β-D-半乳糖苷酶也因炎性小体缺乏而改变。详细的代谢和分子表型表明，在慢性过度喂养过程中，炎性小体控制能量消耗和脂肪形成基因的表达。这些发现揭示了炎性小体在肥胖和胰岛素抵抗中的关键功能，并表明抑制炎性小体作为一种潜在的治疗策略。
Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1 beta and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesity-induced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.