Acute and Long-Term Suppression of Feeding Behavior by POMC Neurons in the Brainstem and Hypothalamus, Respectively
Acute and Long-Term Suppression of Feeding Behavior by POMC Neurons in the Brainstem and Hypothalamus, Respectively
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DOI：
10.1523/jneurosci.2742-12.2013
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发表时间：
2013-02-20
影响因子：
5.3
通讯作者：
Luo, Minmin
中科院分区：
文献类型：
--
作者：
Zhan, Cheng;Zhou, Jingfeng;Luo, Minmin
POMC 衍生的黑皮质素抑制食物摄入。在成年啮齿动物大脑中，表达 POMC 的神经元位于弓状核 (ARC) 和孤束核 (NTS)，但这两个脑核中的 POMC 神经元如何差异调节摄食行为和代谢仍不清楚。在本研究中，我们使用药物遗传学方法激活或消耗不同大脑区域的神经元群，结果表明 ARC 和 NTS 中的 POMC 神经元在不同的时间尺度上抑制进食行为。使用 DREADD（仅由设计药物激活的设计受体）方法激活神经元。通过将 Cre 重组酶依赖性腺相关病毒载体立体定向输注到 POMC-Cre 小鼠的 ARC 或 NTS 中，进化的人类 M3 毒蕈碱受体在选定的 POMC 神经元群体中表达。注射人 M3-毒蕈碱受体配体氯氮平-N-氧化物（1 mg/kg，腹腔注射）后，NTS POMC 神经元的急性激活立即抑制进食行为。相反，ARC POMC 神经元需要长期刺激才能抑制食物摄入。利用腺相关病毒传递白喉毒素受体基因，我们发现白喉毒素诱导ARC而非NTS中的POMC神经元消融，增加食物摄入，减少能量消耗，最终导致肥胖以及代谢和内分泌紊乱。我们的结果揭示了 ARC 和 NTS 中 POMC 神经元的不同行为功能，表明 POMC 神经元通过整合来自下丘脑的长期肥胖信号和来自脑干的短期饱足感信号来调节进食和能量稳态。
POMC-derived melanocortins inhibit food intake. In the adult rodent brain, POMC-expressing neurons are located in the arcuate nucleus (ARC) and the nucleus tractus solitarius (NTS), but it remains unclear how POMC neurons in these two brain nuclei regulate feeding behavior and metabolism differentially. Using pharmacogenetic methods to activate or deplete neuron groups in separate brain areas, in the present study, we show that POMC neurons in the ARC and NTS suppress feeding behavior at different time scales. Neurons were activated using the DREADD (designer receptors exclusively activated by designer drugs) method. The evolved human M3-muscarinic receptor was expressed in a selective population of POMC neurons by stereotaxic infusion of Cre-recombinase-dependent, adeno-associated virus vectors into the ARC or NTS of POMC-Cre mice. After injection of the human M3-muscarinic receptor ligand clozapine-N-oxide (1 mg/kg, i.p.), acute activation of NTS POMC neurons produced an immediate inhibition of feeding behavior. In contrast, chronic stimulation was required for ARC POMC neurons to suppress food intake. Using adeno-associated virus delivery of the diphtheria toxin receptor gene, we found that diphtheria toxin-induced ablation of POMC neurons in the ARC but not the NTS, increased food intake, reduced energy expenditure, and ultimately resulted in obesity and metabolic and endocrine disorders. Our results reveal different behavioral functions of POMC neurons in the ARC and NTS, suggesting that POMC neurons regulate feeding and energy homeostasis by integrating long-term adiposity signals from the hypothalamus and short-term satiety signals from the brainstem.