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 7

Model illustrating proposed neurocircuitry by which ArcN NPY neurons inhibit SNA.

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Model illustrating proposed neurocircuitry by which ArcN NPY neurons inh...
Activation of ArcN NPY (red) neurons (e.g., by either systemic or local CNO administration) inhibits “presympathetic” neurons in both the PVN and DMH, and SNA decreases. The neuropathway by which NPY inputs into the DMH decrease SNA may be mediated in part by a direct projection to the RVLM, but also indirect projections (dashed line). On the other hand, our anatomical data (Figure 2) and previous studies in rats (4) suggest that ArcN-to-PVN NPY inputs directly inhibit presympathetic neurons that project to the RVLM (and possibly also the spinal cord). However, if so, then the failure of blockade of PVN NPY1R to reverse the effects of systemic CNO requires a mechanistic explanation. We hypothesize that reversal of CNO-induced NPY inhibition of PVN presympathetic neurons via PVN NPY1R blockade increases SNA; however, since DMH (and potentially other) neurons that drive the increase in SNA (green neuron) are still inhibited by the CNO-evoked activation of NPY1R, SNA does not reach a maximum. In contrast, we hypothesize that blockade of NPY1R in the DMH unmasks an unfettered excitatory input to RVLM neurons, resulting in a large increase in SNA.