Extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated as important regulators of metabolic homeostasis. Here we generated a new mouse model with genetic deletion of two ERK1/2 phosphatases, dual specificity phosphatase (DUSP) 6 and 8, to further define the role of ERK1/2 in obesity development. Dusp6/8 double-null mice demonstrated elevated ERK1/2 phosphorylation in multiple tissues, without any change of phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). Elevated ERK1/2 activity in Dusp6/8 double-null mice was associated with larger hearts and other organs, consistent with greater rate of cell proliferation in these mice. However, ERK1/2 activation was not sufficient to protect the mouse hearts from pathological hypertrophy and interstitial fibrosis following angiotensin II and phenylephrine stimulation. Interestingly, mice lacking DUSP6/8 were resistant to high-fat diet-induced obesity. Serum triglyceride, lipid content in the liver and visceral adipose tissues was also dramatically reduced in Dusp6/8 double-null mice. Furthermore, Dusp6/8 double-null mice had improved glucose tolerance. Mechanistically, we found out that elevated ERK1/2 activity increased the expression levels of genes involved in lipid metabolism and glucose homeostasis. Together, our data suggest that ERK1/2 play an essential role for the management of metabolic homeostasis.

细胞外信号调节激酶1和2（ERK1 / 2）已被认为是代谢稳态的重要调节剂。在这里，我们生成了具有两个ERK1 / 2磷酸酶，双特异性磷酸酶（DUSP）6和8的遗传缺失的新小鼠模型，以进一步定义ERK1 / 2在肥胖症发展中的作用。Dusp6 / 8双无效小鼠在多个组织中显示ERK1 / 2磷酸化升高，而p38和c-Jun N端激酶（JNKs）的磷酸化没有任何变化。Dusp6 / 8中ERK1 / 2活性升高双无效小鼠与更大的心脏和其他器官相关，这与这些小鼠中较高的细胞增殖率相一致。但是，ERK1 / 2激活不足以保护小鼠心脏免受血管紧张素II和去氧肾上腺素刺激后的病理性肥大和间质纤维化。有趣的是，缺乏DUSP6 / 8的小鼠对高脂饮食诱导的肥胖具有抵抗力。Dusp6 / 8双无效小鼠的血清甘油三酸酯，肝脏和内脏脂肪组织中的脂质含量也显着降低。此外，Dusp6 / 8双无效小鼠具有改善的葡萄糖耐量。从机制上，我们发现升高的ERK1 / 2活性会增加参与脂质代谢和葡萄糖稳态的基因的表达水平。总之，我们的数据表明ERK1 / 2在代谢动态平衡的管理中起着至关重要的作用。