Seo Sanghee, Ju Sunghee, Chung Hyunju, Lee Dahm, Park Seungjoon
Department of Pharmacology, Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, Kyunghee University School of Medicine, Seoul, Korea.
Endocr J. 2008 Oct;55(5):867-74. doi: 10.1507/endocrj.k08e-091. Epub 2008 May 28.
Intracerebroventricular (icv) administration of glucagon-like peptide-1 (GLP-1) inhibits food intake and induces c-fos expression in the hypothalamus. However, the effects of GLP-1 on hypothalamic neuronal activity or neuropeptide mRNA expression are unknown. In this study, we examined the effects of GLP-1 on fasting-induced changes in the expression of hypothalamic orexigenic and anorexigenic neuropeptide. Food intake was significantly inhibited after icv injection of GLP-1 in 48 h fasted rats. Hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNAs were significantly increased by fasting, whereas icv GLP-1 treatment significantly attenuated these fasting-induced increases. Both proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA levels were decreased by fasting, while GLP-1 treatment attenuated fasting-induced decreases in POMC and CART expression. We also determined the mRNA levels of AMP-activated kinase (AMPK) and found that fasting resulted in a significant stimulation of hypothalamic AMPKalpha2 mRNA. Fasting-induced increase in AMPKalpha2 mRNA was almost completely prevented by GLP-1 treatment. Analysis of phosphorylated AMPKalpha and acetyl CoA carboxylase showed similar results. Taken together, our observation suggests that the decreased food intake by GLP-1 is caused by preventing the fasting-induced increase in hypothalamic NPY and AgRP and the fasting-induced decrease in hypothalamic POMC and CART. Our results also suggest that the food intake lowering effect of GLP-1 is caused by reversing the fasting-induced increase in hypothalamic AMPK activity. Therefore we conclude that the anorectic effect of GLP-1 seems to be mediated by, at least in part, by the hypothalamus.
脑室内（icv）注射胰高血糖素样肽-1（GLP-1）可抑制食物摄入并诱导下丘脑c-fos表达。然而，GLP-1对下丘脑神经元活动或神经肽mRNA表达的影响尚不清楚。在本研究中，我们检测了GLP-1对禁食诱导的下丘脑促食欲和抑食欲神经肽表达变化的影响。在禁食48小时的大鼠中，icv注射GLP-1后食物摄入显著受到抑制。禁食显著增加下丘脑神经肽Y（NPY）和刺鼠相关肽（AgRP）的mRNA水平，而icv注射GLP-1处理可显著减弱这些禁食诱导的增加。阿黑皮素原（POMC）和可卡因及苯丙胺调节转录物（CART）的mRNA水平在禁食时均降低，而GLP-1处理可减弱禁食诱导的POMC和CART表达降低。我们还测定了AMP激活的蛋白激酶（AMPK）的mRNA水平，发现禁食可显著刺激下丘脑AMPKα2 mRNA表达。GLP-1处理几乎完全阻止了禁食诱导的AMPKα2 mRNA增加。磷酸化AMPKα和乙酰辅酶A羧化酶的分析显示了类似结果。综上所述，我们的观察结果表明，GLP-1导致食物摄入减少是由于阻止了禁食诱导的下丘脑NPY和AgRP增加以及禁食诱导的下丘脑POMC和CART减少。我们的结果还表明，GLP-1降低食物摄入的作用是通过逆转禁食诱导的下丘脑AMPK活性增加而引起的。因此我们得出结论，GLP-1的抑食欲作用似乎至少部分是由下丘脑介导的。
