Ozaki Kei-Ichi, Awazu Midori, Tamiya Mayuko, Iwasaki Yuka, Harada Aya, Kugisaki Satomi, Tanimura Susumu, Kohno Michiaki
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan; and.
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Am J Physiol Endocrinol Metab. 2016 Apr 15;310(8):E643-E651. doi: 10.1152/ajpendo.00445.2015. Epub 2016 Feb 9.
Extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now examined the potential of pharmacological targeting of the ERK pathway with MEK (ERK kinase) inhibitors (PD184352 and PD0325901) for the treatment of obesity-associated insulin resistance. The effects of PD184352 and PD0325901 on the expression of adipocytokines and lipolysis activity were thus examined in 3T3-L1 adipocytes maintained in long-term culture as a model of adipocyte hypertrophy. Leptin receptor-deficient (db/db) mice and high-fat diet-fed KKAy mice, both of which are models of type 2 diabetes, were also treated orally with PD184352 to examine its effects on the diabetic condition. ERK activity was increased in hypertrophic 3T3-L1 adipocytes as well as in adipose tissue of db/db mice and high-fat diet-fed KKAy mice, and this enhanced ERK signaling was associated with dysregulation of adipocytokine expression and increased lipolysis activity. Specific blockade of the ERK pathway in hypertrophic 3T3-L1 adipocytes by MEK inhibitors ameliorated the dysregulation of adipocytokine expression and suppressed the enhanced lipolysis activity. Furthermore, repeated oral administration of PD184352 normalized hyperglycemia and hyperlipidemia and improved insulin sensitivity and glucose tolerance in the diabetic mice. These results suggest that sustained activation of the ERK pathway in adipocytes is associated with the pathogenesis of type 2 diabetes and that selective blockade of this pathway with MEK inhibitors warrants further study as a promising approach to the treatment of insulin resistance and type 2 diabetes.
细胞外信号调节激酶(ERK)与肥胖和2型糖尿病相关的胰岛素抵抗的发展有关。我们现在研究了用MEK(ERK激酶)抑制剂(PD184352和PD0325901)对ERK途径进行药理学靶向治疗肥胖相关胰岛素抵抗的潜力。因此,在长期培养的3T3-L1脂肪细胞中,以脂肪细胞肥大模型研究了PD184352和PD0325901对脂肪细胞因子表达和脂解活性的影响。瘦素受体缺陷(db/db)小鼠和高脂饮食喂养的KKAy小鼠,这两种都是2型糖尿病模型,也口服PD184352以研究其对糖尿病状况的影响。在肥大的3T3-L1脂肪细胞以及db/db小鼠和高脂饮食喂养的KKAy小鼠的脂肪组织中,ERK活性增加,这种增强的ERK信号与脂肪细胞因子表达失调和脂解活性增加有关。MEK抑制剂对肥大的3T3-L1脂肪细胞中ERK途径的特异性阻断改善了脂肪细胞因子表达的失调,并抑制了增强的脂解活性。此外,重复口服PD184352可使糖尿病小鼠的高血糖和高血脂正常化,并改善胰岛素敏感性和葡萄糖耐量。这些结果表明,脂肪细胞中ERK途径的持续激活与2型糖尿病的发病机制有关,用MEK抑制剂选择性阻断该途径作为治疗胰岛素抵抗和2型糖尿病的一种有前景的方法值得进一步研究。