Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways
Zhigang Shi, … , Christopher J. Madden, Virginia L. Brooks
Zhigang Shi, … , Christopher J. Madden, Virginia L. Brooks
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2868-2880. https://doi.org/10.1172/JCI92008.
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Research Article Metabolism Neuroscience

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Abstract

Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). First, we found that ArcN NPY/AgRP fibers closely appose PVN and DMH presympathetic neurons. Second, nanoinjections of NPY or an NPY receptor Y1 (NPY1R) antagonist into PVN or DMH decreased or increased SSNA, respectively. Third, blockade of DMH NPY1R reversed the sympathoinhibition elicited by selective, DREADD-mediated activation of ArcN NPY/AgRP neurons. Finally, stimulation of ArcN NPY/AgRP terminal fields in the PVN and DMH decreased SSNA. Considering that chronic obesity decreases ArcN NPY content, we propose that the ArcN NPY neuropathway to the PVN and DMH is pivotal in obesity-induced elevations in SNA.

Authors

Zhigang Shi, Christopher J. Madden, Virginia L. Brooks

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Figure 2

Neurons in the PVN, DMH, and LH that project to the RVLM appear to receive inputs from ArcN NPY/AgRP neurons.

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Neurons in the PVN, DMH, and LH that project to the RVLM appear to recei...
CtB-immunoreactive neurons (green) and Ds-red–immunoreactive fibers and terminals in the PVN (A; 52 ± 11 CtB cells, n = 3), DMH (B; 41 ± 18 CtB cells, n = 3), and LH (C; 54 ± 26 CtB cells, n = 3) following injection of CtB in the RVLM (injection sites illustrated in Supplemental Figure 2) and synaptically directed Cre-dependent mCherry expression in ArcN NPY/AgRP neurons. Scale bars: 100 μm. (D) Confocal image of a single plane (192 μm2) illustrating that several PVN neurons that are retrogradely labeled by CtB (green) receive close appositions from ArcN NPY/AgRP fibers and terminals (red). (E and F) Confocal images of single planes (each 112 μm2) illustrating that several scattered CtB-labeled neurons were also observed in the DMH (E) and the LH (F). In the DMH, some of RVLM-projecting neurons also received ArcN NPY/AgRP appositions; however, in the LH these appositions were rare. These images are representative of the results from the 3 mice in which CtB injections encompassed the RVLM. 3V, third ventricle; f, fornix; mt, mamillothalamic tract.