Wu Qi, Howell Maureen P, Cowley Michael A, Palmiter Richard D
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Box 357370, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2687-92. doi: 10.1073/pnas.0712062105. Epub 2008 Feb 13.
Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize gamma-amino-butyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A(y)/a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A(y)/a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.
在成年小鼠中，损毁弓状核内表达抑制性刺鼠相关蛋白（AgRP）且还能合成γ-氨基丁酸（GABA）和神经肽Y的神经元会导致在1周内出现饥饿。预计去除AgRP神经元对相邻阿黑皮素原神经元及其共同的突触后神经元的抑制作用会刺激黑皮质素信号传导，而黑皮质素信号传导已知可抑制食欲。为了研究在该模型中介导饥饿的不受控制的黑皮质素信号传导的重要性，我们在慢性阻断黑皮质素信号传导的A(y)/a小鼠中损毁了AgRP神经元。黑皮质素信号传导的阻断并未改善饥饿速率。在野生型（WT）和A(y)/a两种遗传背景下，AgRP神经元损毁后进食频率均逐渐降低。令人惊讶的是，AgRP神经元损毁后经口进食也显著减少。这些结果表明，AgRP神经元损毁后，进食的食欲和进食行为方面均以与黑皮质素无关的方式受损。
