一个ERK/Cdk5轴控制PPARγγ的糖尿病作用
Alexander S Banks1, Fiona E McAllister2, João Paulo G Camporez3
1Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|November 20, 2014
概括
循环素依赖激酶5 (Cdk5) 通常抑制细胞外信号调节激酶 (ERK),以防止胰岛素抵抗. 抑制MEK/ERK可以改善胰岛素敏感性,为2型糖尿病提供潜在的治疗方法.
科学领域:
- 代谢性疾病研究研究.
- 分子内分泌学分子内分泌学
- 糖尿病的发病原因是糖尿病的病原体.
背景情况:
- 肥胖引起的胰岛素抵抗是2型糖尿病的前体.
- 通过Cdk5在273血清中酸化过酶增殖器激活受体γ (PPARγ),刺激糖尿病基因表达.
- 目前针对PPARγ的抗糖尿病药物抑制了这种酸化.
研究的目的:
- 研究Cdk5在脂肪组织中对PPARγ酸化和胰岛素抵抗的作用.
- 在没有Cdk5.5的情况下,确定负责PPARγ血清273酸化的激酶.
- 探索针对已识别的激酶通路用于2型糖尿病治疗的治疗潜力.
主要方法:
- 产生具有脂肪特异性Cdk5剥离的小鼠.
- 蛋白质组分析以确定淘汰小鼠中的激活激酶.
- 在体内和体外实验中证实ERK对PPARγ的直接酸化.
- 肥胖小鼠模型中MEK和ERK的药理抑制.
主要成果:
- 脂特异性Cdk5剥离矛盾地增加了PPARγ血清273的酸化和胰岛素抵抗的恶化.
- 细胞外信号调节激酶 (ERK) 在Cdk5废除小鼠中被确定为激活激酶.
- 在血清273中,ERK直接酸化PPARγ,而Cdk5则通过MEK抑制ERK活动.
- 药理上抑制MEK/ERK显著改善了肥胖小鼠的胰岛素耐药性,并挽救了Cdk5的废除效应.
结论:
- 一个ERK/Cdk5信号轴在脂肪组织中关键调节PPARγ功能.
- 通过ERK介导的PPARγ酸化有助于胰岛素抵抗.
- 抑制MEK/ERK信号传递是一种有前途的治疗策略,用于2型糖尿病.
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