Howard Hughes Medical Institute and Departments of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Eur J Pharmacol. 2011 Jun 11;660(1):21-7. doi: 10.1016/j.ejphar.2010.10.110. Epub 2011 Jan 3.
The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons-the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) NPY-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (PBN), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6days of DT treatment. Chronic delivery of bretazenil, a GABA(A) receptor partial agonist, into the PBN is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.
下丘脑弓状核包含两个在解剖学和功能上截然不同的神经元群体——刺鼠相关肽（AgRP）和前阿黑皮素原（POMC）表达神经元，它们整合各种营养、激素和神经元信号来调节食物摄入和能量消耗，从而有助于实现能量平衡。AgRP 神经元还共同释放神经肽 Y（NPY）和γ-氨基丁酸（GABA），通过至少三种可能的机制促进进食和抑制代谢：（1）通过 AgRP 与黑素皮质素 4 受体的竞争性结合来抑制黑素皮质素信号系统；（2）NPY 介导对位于下丘脑核中的突触后神经元的抑制；（3）GABA 能抑制其突触后靶标包括臂旁核（PBN）中的 POMC 神经元，PBN 是中继味觉和内脏感觉信息的脑干结构。在成年小鼠中，白喉毒素（DT）的作用可使 AgRP 神经元急性消融，导致食物摄入急剧减少，并在 DT 治疗后 6 天内导致饥饿。当 AgRP 神经元被消融时，将苯二氮䓬受体部分激动剂布雷佐恩（bretazenil）慢性递送至 PBN 足以恢复进食和体重，而慢性阻断黑素皮质素 4 受体信号则是不够的。这篇综述总结了 AgRP 神经元调节的神经回路在控制进食行为中的生理作用，特别强调 GABA 对臂旁核的输出。我们还描述了 AgRP 神经元消融后逐渐参与的一种代偿机制，使小鼠在没有它们的情况下继续进食。
