Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity
Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity
复制标题
DOI：
10.1007/s00125-010-1944-0
复制
发表时间：
2011-01-01
期刊：
影响因子：
8.2
通讯作者：
Tanti, J. F.
中科院分区：
文献类型：
--
作者：
Jager, J.;Corcelle, V.;Tanti, J. F.
细胞外信号调节激酶（ERK）活性在肥胖症和2型糖尿病的脂肪组织中增加，并且强有力的证据表明其涉及胰岛素信号传导和胰岛素抵抗状态中的作用的下调。为了确定ERK 1在体内肥胖相关胰岛素抵抗中的作用，我们在肥胖瘦素缺陷小鼠（ob/ob）中灭活了Erk 1（也称为Mapk 3）。在12周龄的小鼠中研究了葡萄糖耐量和胰岛素敏感性。虽然ob/ob-Erk 1（-/-）和ob/ob小鼠表现出相当的体重和肥胖，但ob/ob-Erk 1（-/-）小鼠没有发生高血糖症，并且它们的葡萄糖耐量得到改善。高胰岛素血症-正常血糖钳夹研究表明，ob/ob-Erk 1（-/-）小鼠全身胰岛素敏感性增加，与骨骼肌中胰岛素刺激的葡萄糖处置和脂肪组织胰岛素敏感性增加相关。这与两种组织中胰岛素信号传导的改善平行发生。ob/ob-Erk 1（-/-）小鼠也部分地保护免于肝脂肪变性，其中乙酰辅酶A羧化酶水平强烈降低。这些代谢改善与脂肪组织中编码炎性细胞因子和T淋巴细胞标志物的mRNA表达减少有关，我们的研究结果表明，ERK 1靶向可以通过减少脂肪组织炎症和增加肌肉葡萄糖摄取来部分保护肥胖小鼠免受胰岛素抵抗和肝脏脂肪变性。我们的研究结果表明，ERK 1通路的失调可能是肥胖相关代谢紊乱的重要组成部分。
Extracellular signal-regulated kinase (ERK) activity is increased in adipose tissue in obesity and type 2 diabetes mellitus and strong evidences suggests that it is implicated in the downregulation of insulin signalling and action in the insulin-resistant state. To determine the role of ERK1 in obesity-associated insulin resistance in vivo, we inactivated Erk1 (also known as Mapk3) in obese leptin-deficient mice (ob/ob).Mice of genotype ob/ob-Erk1 (-/-) were obtained by crossing Erk1 (-/-) mice with ob/ob mice. Glucose tolerance and insulin sensitivity were studied in 12-week-old mice. Tissue-specific insulin sensitivity, insulin signalling, liver steatosis and adipose tissue inflammation were determined.While ob/ob-Erk1 (-/-) and ob/ob mice exhibited comparable body weight and adiposity, ob/ob-Erk1 (-/-) mice did not develop hyperglycaemia and their glucose tolerance was improved. Hyperinsulinaemic-euglycaemic clamp studies demonstrated an increase in whole-body insulin sensitivity in the ob/ob-Erk1 (-/-) mice associated with an increase in both insulin-stimulated glucose disposal in skeletal muscles and adipose tissue insulin sensitivity. This occurred in parallel with improved insulin signalling in both tissues. The ob/ob-Erk1 (-/-) mice were also partially protected against hepatic steatosis with a strong reduction in acetyl-CoA carboxylase level. These metabolic improvements were associated with reduced expression of mRNA encoding inflammatory cytokine and T lymphocyte markers in the adipose tissue.Our results demonstrate that the targeting of ERK1 could partially protect obese mice against insulin resistance and liver steatosis by decreasing adipose tissue inflammation and by increasing muscle glucose uptake. Our results indicate that deregulation of the ERK1 pathway could be an important component in obesity-associated metabolic disorders.