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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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 5

Bilateral nanoinjection of CNO into the PVN or DMH of ArcN hM3Dq mice decreases SSNA, HR, and MAP, and these responses are reversed by subsequent PVN or DMH injections of BIBO3304.

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Bilateral nanoinjection of CNO into the PVN or DMH of ArcN hM3Dq mice de...
(A) Representative experiment showing that PVN CNO decreases SSNA in an ArcN hM3Dq mouse. (B) Representative experiment showing that DMH CNO decreases SSNA in an ArcN hM3Dq mouse. (C) Histological sections illustrating hM3Dq mCherry-labeled fibers from ArcN NPY/AgRP neurons and fluorescent injected beads in the PVN (left) and DMH (middle). The right panel shows an injection that missed the DMH. White arrows point to injection sites. Scale bars: 200 μm. (D) Group data showing that PVN or DMH CNO similarly decreases SSNA, HR, and MAP, but CNO injections that miss these targets or aCSF injections do not. Red symbols, DMH injections; blue symbols, PVN injections; black triangles, missed injections. Analyzed using 2-way repeated-measures ANOVA. (E) Representative experiment showing that PVN CNO decreases SSNA in a mouse harboring h3MDq in NPY/AgRP fibers, and this is reversed by PVN BIBO3304. (F) Grouped data showing that PVN BIBO3304 reverses the effects of PVN CNO. (G) Representative experiment showing that DMH CNO decreases SSNA in a mouse harboring h3MDq in NPY/AgRP fibers, and this is reversed by DMH BIBO3304. (H) Grouped data showing that DMH BIBO3304 reverses the effects of DMH CNO. In F and H, arrows indicate the times at which CNO, and then BIBO3304, were injected. Data in F and H were analyzed using 1-way repeated-measures ANOVA. Baseline values were 82 ± 3 mmHg and 492 ± 13 bpm (single PVN or DMH nanoinjections; n = 25), 81 ± 3 mmHg and 461 ± 21 bpm (PVN CNO, followed by PVN BIBO3304; n = 7), and 85 ± 3 mmHg and 452 ± 24 bpm (DMH CNO followed by DMH BIBO3304; n = 5). (I) Histological maps illustrating PVN and DMH injection sites (based on ref. 80). *P < 0.05, compared with time 0.