Qi Ling, Saberi Maziyar, Zmuda Erik, Wang Yiguo, Altarejos Judith, Zhang Xinmin, Dentin Renaud, Hedrick Susie, Bandyopadhyay Gautam, Hai Tsonwin, Olefsky Jerry, Montminy Marc
Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cell Metab. 2009 Mar;9(3):277-86. doi: 10.1016/j.cmet.2009.01.006.
Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.
肥胖程度增加会引发代谢和炎症变化，干扰外周组织中的胰岛素作用，最终导致β细胞功能衰竭和显性糖尿病。我们发现，环磷酸腺苷反应元件结合蛋白（CREB）在肥胖条件下的脂肪细胞中被激活，它通过触发转录抑制因子ATF3的表达来促进胰岛素抵抗，从而下调脂肪因子激素脂联素以及胰岛素敏感的葡萄糖转运蛋白4（GLUT4）的表达。在脂肪细胞中表达显性负性CREB转基因的转基因小鼠在饮食诱导和基因肥胖的情况下表现出全身胰岛素敏感性增加，并且它们能够预防肝脂肪变性和脂肪组织炎症的发展。这些结果表明，脂肪细胞中的CREB在2型糖尿病的进展中提供了一个早期信号。
