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 1

Selective activation and inhibition of ArcN NPY/AgRP neurons decreases and increases SNA, respectively.

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Selective activation and inhibition of ArcN NPY/AgRP neurons decreases a...
(A) Representative experiment showing that i.p. injection of saline (at thin arrow) has no effect on raw SSNA, HR, and MAP in an ArcN hM3Dq mouse. Expanded raw nerve tracings, before and after injection, are indicated in this and all subsequent figures by filled and open arrows, respectively. (B) Representative experiment showing that i.p. injection of CNO (at thin arrow) in an ArcN hM3Dq mouse immediately decreases raw SSNA, HR, and MAP. (C) Grouped data showing that i.p. CNO, but not saline, decreases SSNA, HR, and MAP in ArcN hM3Dq mice. Neither saline nor CNO had effects in WT mice that received hM3Dq. Baseline values in WT mice (n = 13) were 88 ± 3 mmHg and 469 ± 13 bpm and in Agrp-IRES-Cre (n = 12) were 91 ± 3 mmHg and 460 ± 16 bpm. (D). Representative experiment showing that i.p. injection of saline (at thin arrow) has no effect on raw SSNA, HR, and MAP in an ArcN hM4Di mouse. (E) Representative experiment showing that i.p. injection of CNO (at thin arrow) in an ArcN hM4Di mouse increases raw SSNA, HR, and MAP. (F). Grouped data showing that i.p. CNO, but not saline, dose-dependently increases SSNA, HR, and MAP in ArcN hM4Di mice. Baseline values were 78 ± 3 mmHg and 466 ± 14 bpm (n = 11). *P < 0.05, compared with time 0.