Chiang Shian-Huey, Bazuine Merlijn, Lumeng Carey N, Geletka Lynn M, Mowers Jonathan, White Nicole M, Ma Jing-Tyan, Zhou Jie, Qi Nathan, Westcott Dan, Delproposto Jennifer B, Blackwell Timothy S, Yull Fiona E, Saltiel Alan R
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Cell. 2009 Sep 4;138(5):961-75. doi: 10.1016/j.cell.2009.06.046.
Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-kappaB activation in mice, which leads to a sustained elevation in level of IkappaB kinase epsilon (IKKepsilon) in liver, adipocytes, and adipose tissue macrophages. IKKepsilon knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKepsilon knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKepsilon may represent an attractive therapeutic target for obesity, insulin resistance, diabetes, and other complications associated with these disorders.
肥胖与慢性低度炎症相关，这种炎症会对胰岛素敏感性产生负面影响。在此，我们表明高脂饮食可增加小鼠体内的核因子κB（NF-κB）激活，这会导致肝脏、脂肪细胞和脂肪组织巨噬细胞中κB激酶ε（IKKε）水平持续升高。IKKε基因敲除小鼠可免受高脂饮食诱导的肥胖、肝脏和脂肪中的慢性炎症、肝脂肪变性以及全身胰岛素抵抗。这些小鼠通过增强解偶联蛋白UCP1的表达而表现出能量消耗增加和产热增加。它们在肝脏和脂肪中维持胰岛素敏感性，而不会激活促炎的JNK途径。基因表达分析表明，IKKε基因敲除可降低炎性细胞因子的表达，并改变参与葡萄糖和脂质代谢的某些调节蛋白和酶的表达。因此，IKKε可能是肥胖、胰岛素抵抗、糖尿病以及与这些疾病相关的其他并发症的一个有吸引力的治疗靶点。
