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 4

Bilateral nanoinjection of BIBO3304 into the DMH, but not the PVN, reverses the effects of select activation of ArcN NPY/AgRP neurons.

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Bilateral nanoinjection of BIBO3304 into the DMH, but not the PVN, rever...
(A) Representative experiment in an ArcN hM3Dq mouse showing that PVN BIBO3304 increases SSNA after i.p. CNO. (B and C) Grouped data illustrate the time course of changes in SSNA, HR, and MAP (B), and the results of 2-way ANOVA (C) show that i.p. CNO, but not i.p. saline, significantly decreases SSNA, HR, and MAP. Subsequent PVN BIBO3304 increased these variables in both groups; however, SSNA, HR, and MAP in mice given i.p. CNO remained below values obtained in mice given i.p. saline. On the other hand, the responses to i.p. CNO remained stable after PVN aCSF injections. Baseline values were 89 ± 3 mmHg and 486 ± 12 bpm (n = 15). (D) Histological maps illustrating PVN injection sites. (E) Representative experiment showing that DMH BIBO3304 increases SSNA after i.p. CNO in an ArcN hM3Dq mouse. (F and G) Grouped data illustrate the time course of changes in SSNA, HR, and MAP (F), and the results of 2-way repeated-measures ANOVA (G) show that i.p. CNO, but not i.p. saline, significantly decreased SSNA, HR, and MAP; subsequent DMH BIBO3304 significantly increased these variables to the same levels in both groups. On the other hand, the responses to i.p. CNO remained stable after DMH aCSF injections. Baseline values were 88 ± 3 mmHg and 456 ± 14 bpm (n = 13). (H) Histological maps illustrating DMH injection sites. *P < 0.05, compared with time 0; †P < 0.05 compared with previous value within group; ‡P < 0.05 between groups receiving i.p. saline versus i.p. CNO and PVN/DMH BIBO3304; #P < 0.05 between groups receiving i.p. CNO and PVN/DMH aCSF versus i.p. CNO and PVN/DMH BIBO3304.