Nigrostriatal rAAV-mediated GDNF Overexpression Induces Robust Weight Loss in a Rat Model of Age-related Obesity
Nigrostriatal rAAV-mediated GDNF Overexpression Induces Robust Weight Loss in a Rat Model of Age-related Obesity
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DOI：
10.1038/mt.2009.45
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发表时间：
2009-06-01
影响因子：
12.4
通讯作者：
Mandel, Ronald J.
中科院分区：
文献类型：
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作者：
Manfredsson, Fredric P.;Tumer, Nihal;Mandel, Ronald J.
脑室内注射胶质细胞源性神经营养因子（GDNF）在灵长类动物和人类中研究帕金森病（PD）揭示了GDNF诱导体重减轻的潜力。我们以前的数据表明，通过重组腺相关病毒（rAAV）的双边连续下丘脑GDNF过表达的结果显着失败，在年轻大鼠体重增加和老年大鼠体重减轻。基于这些先前的结果，我们假设，因为黑质纹状体束通过外侧下丘脑，运动过度活跃介导的黑质纹状体多巴胺（DA）可能是负责先前观察到的影响体重。在这项研究中，我们比较了老年Brown-Norway X Fisher 344大鼠下丘脑与黑质（SN）中双侧注射rAAV 2/5-GDNF。黑质纹状体GDNF过度表达导致的体重减轻明显大于下丘脑。黑质或下丘脑GDNF诱导的体重减轻与大鼠的运动活动水平无关，尽管一些体重减轻可能归因于食物摄入的短暂减少。前脑DA水平并没有解释观察到的对体重的影响，虽然GDNF诱导的中脑核DA的增加可能部分促成了下丘脑GDNF治疗组的这种效果。然而，只有黑质纹状体GDNF过表达诱导磷酸化细胞外信号调节激酶（p-ERK）在一小群促肾上腺皮质激素释放因子[促肾上腺皮质激素释放激素（CRH）]神经元的激活，特别是位于内侧小细胞分裂（MPD）的下丘脑室旁核。这些下丘脑CRH神经元的激活可能解释了所观察到的导致肥胖大鼠体重减轻的代谢效应。
Intraventricular administration of glial cell line-derived neurotrophic factor (GDNF) in primate and humans to study Parkinson's disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight. In this study, we compared bilateral injections of rAAV2/5-GDNF in hypothalamus versus substantia nigra (SN) in aged Brown-Norway X Fisher 344 rats. Nigrostriatal GDNF overexpression resulted in significantly greater weight loss than rats treated in hypothalamus. The nigral or hypothalamic GDNF-induced weight loss was unrelated to motor activity levels of the rats, though some of the weight loss could be attributed to a transient reduction in food intake. Forebrain DA levels did not account for the observed effects on body weight, although GDNF-induced increases in nucleus accumbens DA may have partially contributed to this effect in the hypothalamic GDNF-treated group. However, only nigrostriatal GDNF overexpression induced activation of phosphorylated extracellular signal-regulated kinase (p-ERK) in a small population of corticotrophin-releasing factor [corticotrophin-releasing hormone (CRH)] neurons located specifically in the medial parvocellullar division (MPD) of the paraventricular nucleus of the hypothalamus. Activation of these hypothalamic CRH neurons likely accounted for the observed metabolic effects leading to weight loss in obese rats.