Department of Physiology/Metabolic Physiology (J.E.R., R.H.A., K.P.S.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-40530, Sweden; Laboratory of Endocrine Neurobiology (I.F., Z.L.), Institute of Experimental Medicine, Budapest 1083, Hungary; Department of Physiology/Endocrinology (F.A., S.L.D., J.-O.J.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-40530, Sweden; and Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Institute of Metabolic Science (F.M.G., F.R.), University of Cambridge, Cambridge CB2 2XY, United Kingdom.
Endocrinology. 2014 Nov;155(11):4356-67. doi: 10.1210/en.2014-1248. Epub 2014 Aug 13.
The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.
脑桥臂旁核（PBN）是调节进食行为的关键核团。来自下丘脑的抑制性输入对 PBN 正常维持进食行为起着至关重要的作用，因为它们的缺失会导致饥饿。内脏感觉刺激会导致 PBN 的神经元激活。然而，兴奋神经元输入到 PBN 的起源和神经化学特性在很大程度上仍未得到探索。在这里，我们假设脑桥 GLP-1（胰高血糖素样肽 1）神经元向 PBN 提供兴奋性输入，其激活可能导致进食行为减少。我们的数据来自于在 GLP-1 产生神经元中表达黄色荧光蛋白的小鼠，结果显示脑桥 GLP-1 产生神经元投射到外侧 PBN（lPBN）。刺激 lPBN GLP-1 受体（GLP-1Rs）可减少大鼠的 Chow 和美味食物摄入量，并降低体重。它还激活了 lPBN 神经元，这反映在该区域中 c-Fos 阳性细胞数量的增加。电生理研究进一步支持 GLP-1 在 PBN 中的兴奋性作用，表明 Exendin-4 应用后 lPBN 神经元的放电显著增加。我们表明，在 PBN 内，GLP-1R 激活增加了两种能量平衡调节肽的基因表达，即降钙素基因相关肽（CGRP）和白细胞介素 6（IL-6）。此外，近 70%的 lPBN GLP-1 纤维支配 lPBN CGRP 神经元。直接向 lPBN 内注射 CGRP 会导致厌食。总的来说，我们的分子、解剖、电生理、药理学和行为学数据为 GLP-1R 在 PBN 中控制进食的功能作用提供了证据。
