Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity.
Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity.
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作者：
Feng B;Jiao P;Helou Y;Li Y;He Q;Walters MS;Salomon A;Xu H
丝裂原活化蛋白激酶磷酸酶3（MKP-3）是细胞外信号相关激酶信号传导的负调节剂。我们的实验室最近证明，MKP-3通过促进肝脏葡萄糖输出在肥胖相关的高血糖中起重要作用。这项研究表明，MKP-3缺乏减弱了由高脂饮食（HFD）诱导的体重增加，并保护小鼠免于发生肥胖相关的脂肪肝。与野生型（WT）对照组相比，喂食HFD的MKP-3−/−小鼠肝脏中的甘油三酯（TG）含量显著降低。MKP-3的缺乏也可能通过抑制脂肪细胞分化来减少肥胖。此外，MKP-3−/−小鼠表现出能量消耗增加，外周葡萄糖处理增强，全身胰岛素敏感性改善。我们进行了全球磷酸化蛋白质组学研究，以寻找MKP-3在肝脏脂质代谢中作用的下游介质。我们的研究结果表明，MKP-3缺陷使组蛋白脱乙酰基酶（HDAC）1在丝氨酸393上的磷酸化增加3.3倍，使HDAC 2在丝氨酸394上的磷酸化增加2.33倍。在喂食HFD的MKP-3−/−小鼠的肝脏中，HDAC 1和2的活性增加。HDAC 1/2活性的降低足以使MKP-3−/−原代肝细胞的TG含量恢复至与WT细胞相似的水平。
Mitogen-activated protein kinase phosphatase 3 (MKP-3) is a negative regulator of extracellular signal–related kinase signaling. Our laboratory recently demonstrated that MKP-3 plays an important role in obesity-related hyperglycemia by promoting hepatic glucose output. This study shows that MKP-3 deficiency attenuates body weight gain induced by a high-fat diet (HFD) and protects mice from developing obesity-related hepatosteatosis. Triglyceride (TG) contents are dramatically decreased in the liver of MKP-3−/− mice fed an HFD compared with wild-type (WT) controls. The absence of MKP-3 also reduces adiposity, possibly by repressing adipocyte differentiation. In addition, MKP-3−/− mice display increased energy expenditure, enhanced peripheral glucose disposal, and improved systemic insulin sensitivity. We performed global phosphoproteomic studies to search for downstream mediators of MKP-3 action in liver lipid metabolism. Our results revealed that MKP-3 deficiency increases the phosphorylation of histone deacetylase (HDAC) 1 on serine 393 by 3.3-fold and HDAC2 on serine 394 by 2.33-fold. Activities of HDAC1 and 2 are increased in the livers of MKP-3−/− mice fed an HFD. Reduction of HDAC1/2 activities is sufficient to restore TG content of MKP-3−/− primary hepatocytes to a level similar to that in WT cells.
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