Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State
Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State
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DOI：
10.1016/j.cmet.2018.10.016
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发表时间：
2019-03-05
期刊：
影响因子：
29
通讯作者：
Krashes, Michael J.
中科院分区：
文献类型：
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作者：
Li, Chia;Navarrete, Jovana;Krashes, Michael J.
了解食欲控制背后的神经框架对于开发对抗肥胖流行的有效疗法至关重要。室旁下丘脑 (PVH) 对于食欲调节至关重要，然而，PVH 神经元对营养物质的实时生理反应特性尚不清楚。结合光纤光度测定、电生理学、免疫组织化学和神经操作策略，我们确定了与摄食行为有关的四种分子描述的 PVH 子集的群体动态：胰高血糖素样肽 1 受体 (PVHGlp1r)、黑皮质素 4 受体 (PVHMc4r)、催产素 (PVHOxt) 和促肾上腺皮质激素释放激素 (PVHCrh)。我们分别确定了 PVHGlp1r 和 PVHCrh 群体中卡路里和状态依赖性持续活性的增加和减少，同时观察 PVHMc4r 的瞬时总体变化，但 PVHOxt 神经元对食物没有反应。此外，我们强调了PVHGlp1r神经元在协调急性进食行为中的作用，独立于抗肥胖药物利拉鲁肽，并证明PVHGlp1r和PVHMc4r（而不是PVHOxt或PVHCrh神经元）在体重维持中不可或缺。
Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance.