Department of Pathology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio;
Am J Physiol Endocrinol Metab. 2013 Aug 15;305(4):E549-56. doi: 10.1152/ajpendo.00197.2013. Epub 2013 Jul 16.
Saturated fatty acids activate the c-Jun NH₂-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro; however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here, we have used MLK3-deficient mice to examine the role of MLK3 in a saturated-fat diet model of obesity. MLK3-KO mice fed a high-fat diet enriched in medium-chain saturated fatty acids for 16 wk had decreased body fat compared with wild-type (WT) mice due to increased energy expenditure independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow-derived macrophages in vitro, and obesity induced JNK activation, macrophage infiltration into adipose tissue, and expression of proinflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction.
饱和脂肪酸激活 c-Jun NH₂-末端激酶（JNK）通路，导致慢性低度炎症和胰岛素抵抗的发展。混合谱系激酶 3（MLK3）是丝裂原活化蛋白激酶激酶激酶（MAP3K），可介导体外饱和脂肪酸诱导的 JNK 激活；然而，体内饮食诱导的 JNK 激活的确切机制尚不清楚。在这里，我们使用 MLK3 缺陷小鼠来研究 MLK3 在肥胖的饱和脂肪饮食模型中的作用。与野生型（WT）小鼠相比，用富含中链饱和脂肪酸的高脂肪饮食喂养 16 周的 MLK3-KO 小鼠由于能量消耗增加而导致体脂减少，而与食物消耗和体力活动无关。此外，MLK3 缺乏可减弱体外棕榈酸诱导的骨髓来源巨噬细胞中 JNK 激活和 M1 极化，以及体内肥胖诱导的 JNK 激活、巨噬细胞浸润脂肪组织和促炎细胞因子的表达。此外，缺失 MLK3 可改善胰岛素抵抗和减少肝脂肪变性。总之，这些数据表明 MLK3 促进体内饱和脂肪酸诱导的 JNK 激活和饮食诱导的代谢功能障碍。
