Lentivirus-mediated downregulation of hypothalamic insulin receptor expression
Lentivirus-mediated downregulation of hypothalamic insulin receptor expression
复制标题
DOI：
10.1016/j.physbeh.2007.05.043
复制
发表时间：
2007-11-23
影响因子：
2.9
通讯作者：
Reagan, L. P.
中科院分区：
文献类型：
--
作者：
Grillo, C. A.;Tamashiro, K. L.;Reagan, L. P.
调节进食行为和能量平衡是胰岛素的主要作用。例如，脑室内施用胰岛素减少食物摄入和体重，而胰岛素受体（IR）的反义寡脱氧核苷酸下调产生食欲过盛。为了进一步研究IR在胰岛素中枢作用中的作用，我们设计了IR反义慢病毒载体（LV-IRAS），并将该载体注射到第三脑室中以选择性地降低大鼠下丘脑中的IR表达。LV-IRAS给药3周后，下丘脑中IR的表达显著降低，而海马IR水平无变化。LV-IRAS给药降低了胰岛素刺激的下丘脑IR磷酸化和下丘脑中胰岛素敏感性葡萄糖转运蛋白GLUT 4的易位;在LV-IRAS给药大鼠的海马中未观察到IR信号传导的变化。慢病毒介导的IR表达和信号转导的下调产生了体重的显著增加，以及对皮下隔室具有选择性的脂肪量的增加。相反，与用对照病毒处理的大鼠相比，LV-IRAS处理的大鼠的瘦肌肉质量和水质量不受影响。在LV-IRAS大鼠中，在瘦素受体表达没有变化的情况下，外周肥胖的变化与基础下丘脑瘦素信号的增加相关。总的来说，这些数据说明了下丘脑胰岛素和瘦素信号在调节身体组成中的重要功能关系，并提供了深入了解IR表达和信号传导减少使瘦素活性失调，从而促进外周肥胖增加的机制。(C)2007年爱思唯尔公司All rights reserved.
Regulation of feeding behavior and energy balance are among the central effects of insulin. For example, intracerebroventricular administration of insulin decreases food intake and body weight, whereas antisense oligodeoxynucleotide downregulation of insulin receptors (IRs) produces hyperphagia. To further examine the role of IRs in the central actions of insulin, we designed an IR antisense lentiviral vector (LV-IRAS) and injected this vector into the third ventricle to selectively decrease IR expression in the rat hypothalamus. Three weeks after LV-IRAS administration, the expression of IRs in the hypothalamus was significantly decreased, whereas no changes were observed in hippocampal IR levels. LV-IRAS administration decreased insulin-stimulated phosphorylation of hypothalamic IRs and translocation of the insulin-sensitive glucose transporter GLUT4 in the hypothalamus; no changes in IR signaling were observed in the hippocampus of LV-IRAS-treated rats. Lentivirus-mediated downregulation of IR expression and signaling produced significant increases in body weight, as well as increases in fat mass that were selective for the subcutaneous compartment. Conversely, lean muscle mass and water mass were not affected in LV-IRAS-treated rats compared to rats treated with control virus. Changes in peripheral adiposity were associated with increases in basal hypothalamic leptin signaling in the absence of changes in leptin receptor expression in LV-IRAS rats. Collectively, these data illustrate the important functional relationships between hypothalamic insulin and leptin signaling in the regulation of body composition and provide insight into the mechanisms through which decreases in IR expression and signaling dysregulates leptin activity, thereby promoting increases in peripheral adiposity. (C) 2007 Elsevier Inc. All rights reserved.