Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
Endocrinology. 2011 Jul;152(7):2558-67. doi: 10.1210/en.2010-1407. Epub 2011 May 17.
Angiopoietin-like (Angptl)2, a member of the Angptl protein family, is predominantly secreted from adipose tissue and the heart. Here, we demonstrate that the expression of Angptl2 in epididymal adipose tissue of C57BL/6J mice shows pulsatility and circadian rhythmicity and that the rhythmicity was disrupted in high-fat-fed and leptin receptor-deficient diabetic db/db mice with insulin resistance. To investigate whether the reduction in Angptl2 expression was related to the progression of diabetes, we treated db/db mice with recombinant Angptl2 for 4 wk during the peak period of Angptl2 expression in C57BL/6J mice. Angptl2-treated mice showed decreases in plasma glucose, insulin, triglyceride, and fatty acid levels and an increase in plasma adiponectin, a therapeutic regulator of insulin resistance, leading to improvements in glucose tolerance. In cultured adipocytes, recombinant Angptl2 increased adiponectin expression and stimulated insulin sensitivity partially by reducing the levels of tribbles homolog 3, a specific Akt kinase inhibitory protein. Conversely, Angptl2 small interfering RNA reduced adiponectin expression, resulting in insulin resistance. In preadipocytes, treatment with Angptl2 small interfering RNA inhibited differentiation to adipocytes and reduced adiponectin expression. Taken together, our results suggest that replenishment of Angptl2 stimulates insulin sensitivity and improves the type 2 diabetic state.
血管生成素样蛋白 2（Angptl2）是血管生成素蛋白家族的成员，主要从脂肪组织和心脏分泌。在这里，我们证明 C57BL/6J 小鼠附睾脂肪组织中 Angptl2 的表达具有脉冲性和昼夜节律性，而在高脂肪喂养和瘦素受体缺陷的糖尿病 db/db 小鼠中，这种节律性被破坏，这些小鼠伴有胰岛素抵抗。为了研究 Angptl2 表达的减少是否与糖尿病的进展有关，我们在 C57BL/6J 小鼠 Angptl2 表达的高峰期用重组 Angptl2 治疗 db/db 小鼠 4 周。Angptl2 治疗的小鼠表现出血浆葡萄糖、胰岛素、甘油三酯和脂肪酸水平降低，血浆脂联素升高，脂联素是胰岛素抵抗的治疗调节剂，导致葡萄糖耐量改善。在培养的脂肪细胞中，重组 Angptl2 通过降低 Akt 激酶特异性抑制蛋白 tribbles 同源物 3（tribbles homolog 3，一种 Akt 激酶特异性抑制蛋白）的水平，增加脂联素的表达并刺激胰岛素敏感性。相反，Angptl2 小干扰 RNA 降低脂联素的表达，导致胰岛素抵抗。在前体脂肪细胞中，Angptl2 小干扰 RNA 的处理抑制脂肪细胞的分化，并降低脂联素的表达。总之，我们的结果表明，Angptl2 的补充刺激胰岛素敏感性并改善 2 型糖尿病状态。
