Hsieh Yih-Shou, Yang Shun-Fa, Chu Shu-Chen, Kuo Dong-Yih
Institute of Biochemistry, Central Taiwan University of Science and Technology, Taichung City, Taiwan, Republic of China.
Physiol Genomics. 2007 Oct 22;31(2):306-14. doi: 10.1152/physiolgenomics.00110.2007. Epub 2007 Aug 7.
Neuropeptide Y (NPY) is an appetite-controlling neuromodulator that contributes to the appetite-suppressing effect of phenylpropanolamine (PPA). Aims of this study were to investigate whether protein kinase A (PKA) signaling is involved in regulating NPY gene expression and PPA-induced anorexia. Rats were given daily with PPA for 5 days. Changes in daily food intake and hypothalamic NPY, PKA, cAMP response element binding protein (CREB), and pro-opiomelanocortin (POMC) gene expression were measured and compared. To further determine if PKA was involved, intracerebroventricular infusions of antisense oligodeoxynucleotide were performed at 60 min before daily PPA treatment in freely moving rats. Results showed that daily PKA, CREB, and POMC expression were increased following PPA treatment, which showed a closely reverse relationship with alterations of decreased feeding behaviors and NPY mRNA levels. Results also showed that PKA knock-down could block PPA-induced anorexia as well as restore NPY mRNA level, indicating the involvement of PKA signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of hypothalamic NPY gene expression. The present findings reveal that manipulations at the molecular level of PKA or cAMP may allow the development of therapeutic agents to improve the undesirable properties of PPA or other amphetamine-like anorectic drugs.
神经肽Y（NPY）是一种控制食欲的神经调节剂，它有助于苯丙醇胺（PPA）的食欲抑制作用。本研究的目的是调查蛋白激酶A（PKA）信号通路是否参与调节NPY基因表达和PPA诱导的厌食症。给大鼠每日注射PPA，持续5天。测量并比较每日食物摄入量以及下丘脑NPY、PKA、环磷酸腺苷反应元件结合蛋白（CREB）和阿黑皮素原（POMC）基因表达的变化。为了进一步确定PKA是否参与其中，在自由活动的大鼠每日接受PPA治疗前60分钟进行脑室内注射反义寡脱氧核苷酸。结果显示，PPA治疗后，每日PKA、CREB和POMC表达增加，这与进食行为减少和NPY mRNA水平的变化呈密切的反向关系。结果还显示，敲低PKA可以阻断PPA诱导的厌食症，并恢复NPY mRNA水平，表明PKA信号通路参与NPY基因表达的调节。提示下丘脑PKA信号通路可能通过调节下丘脑NPY基因表达参与PPA介导的食欲抑制的中枢调节。本研究结果表明，对PKA或环磷酸腺苷进行分子水平的调控可能有助于开发治疗药物，以改善PPA或其他苯丙胺类厌食药的不良特性。
