Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation

Cassaglia, Priscila A.; Shi, Zhigang; Li, Baoxin; Reis, Wagner Luis; Clute-Reinig, Nicholas M.; Stern, Javier E.; Brooks, Virginia L.

doi:10.1113/jphysiol.2013.268763

Cited by 35 publications

(67 citation statements)

References 65 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 47%

“…In contrast, the role of this neuronal population in the control of SNA had been largely unexplored, despite recent evidence that NPY acts in the PVN to inhibit SNA (4,5,26) and that NPY/ AgRP neurons project to the PVN (9,16,19). Here, via DREADD methodology, we demonstrate that ArcN AgRP/NPY neurons tonically suppress SNA, MAP, and HR.…”

Section: Discussionmentioning

confidence: 84%

“…In rats, the hypothalamic paraventricular nucleus (PVN) is a major site of action, at which NPY directly inhibits presympathetic neurons that project to the rostral ventrolateral medulla (RVLM), which drives basal sympathetic tone (4). Nevertheless, the sources of NPY inputs to PVN that elicit sympathoinhibition have not been identified.…”

Section: Introductionmentioning

confidence: 99%

“…Immunohistochemistry was performed as previously described (4,26,81). The primary antibodies used in these studies included rabbit antidsRed, which detects mCherry (1:2,500; catalog 632496, Clontech), rabbit anti-mCherry (1:1,000; ab167453, Abcam), and goat anti-CtB (1:10,000; product 703, List Biological Laboratories).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ArcN) are key contributors (3). However, POMC-induced sympathoexcitation requires simultaneous withdrawal of tonic neuropeptide Y (NPY) inhibition (4,5). Thus, NPY acts as a critical gatekeeper for the excitatory inputs that drive sympathoexcitation, suggesting that suppressed NPY inhibition must occur in parallel to increased POMC excitation with obesity.…”

Section: Introductionmentioning

confidence: 99%

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Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Shi¹,

Madden²,

Brooks³

2017

Journal of Clinical Investigation

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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 The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 8 6 9 jci.org Volume 127 Number 7 July 2017We next tested whether selective excitation or inhibition of ArcN NPY/AgRP neurons alters splanchnic SNA (SSNA), mean AP (MAP), or heart rate (HR) ( Figure 1). As shown in representative experiments ( Figure 1, A and B) and grouped data ( Figure 1C), in ArcN hM3Dq mice, i.p. CNO (0.3 mg/kg) promptly decreased SSNA, MAP, and HR, whereas i.p. saline had no effects. The suppression induced by CNO was sustained for at least 1 hour, and, in mice with longer recordings, up to 4 hours (data not shown). In rats, guinea pigs, and humans, CNO can have nonspecific effects due to its conversion to clozapine (17, 18). However, in WT mice receiving the Cre-dependent hM3Dq vector, neither i.p. saline nor CNO significantly altered these variables, suggesting that CNO was not exerting its effects independently of DREADD activation. A separate group of Agrp-IRES-Cre mice instead received AAV-hM4Di-mCherry in the ArcN (Figure 1, D-F). In these ArcN hM4Di mice, i.p. CNO (0.3 and 1 mg/kg) dose-dependently increased SSNA, MAP, and HR, although the responses developed both NPY-GFP and Cre in AgRP neurons. In agreement with an earlier study using a different approach (14), we found that while not all NPY-GFP neurons had visible hM3Dq-mCherry labeling, 100% of the hM3Dq-mCherry-marked neurons also expressed NPY-GFP (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI92008DS1). WT mice never expressed the Cre-dependent DREADD. In a second set of experiments, 2 or more weeks after Agrp-IRES-Cre mice received hM3Dq bilaterally in the ArcN, CNO (0.3 mg/kg) or the saline vehicle was administered i.p., and food intake was monitored for the following 4 hours. As shown previously (14), i.p. CNO, but not saline, rapidly evoked food intake in ArcN hM3Dq mice (Supplemental Figure 1). Conversely, activation of inhibitory DREADDs in ArcN hM4Di mice at the beginning of the feeding period (lights out) inhibited food intake (Supplemental Figure 1). Therefore, we anatomically and functionally confirm that this approach selectively targets ArcN NPY/AgRP neurons. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 8 7 0jci.org Volume 127 Number 7 July 2017neurons were also observ...

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Shi¹,

Madden²,

Brooks³

2017

Journal of Clinical Investigation

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Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

Parker

Shen

Wearne

et al. 2017

J of Comparative Neurology

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Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed.

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Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice

Fink

Guo

Kulkarni

et al. 2017

Pharmacol Res Perspect

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We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain, decreased food intake, increased hypothalamic orexigenic gene expression, and mitigated oxidative stress when administered from the onset of high‐fat (HF) feeding. Here, we examined the effects of mitoQ on pre‐existing obesity in C57BL/6J mice first made obese by 107 days of HF feeding. In contrast to our preventative study, we found that already obese mice did not tolerate mitoQ at 500 μmol/L. Within 4 days of administration, obese mice markedly decreased food and water intake and lost substantial weight necessitating a dose reduction to 250 μmol/L. Food and water intake then improved. Over the next 4 weeks, body mass of the mitoQ‐treated mice increased faster than vehicle‐treated controls but did not catch up. Over the subsequent 10 weeks, weights of the mitoQ‐treated group remained significantly less than vehicle control, but percent fat and food intake did not differ. Although the mitoQ‐treated groups continued to drink less, there was no difference in percent body fluid and no laboratory evidence of dehydration at study end. At the time of killing, hypothalamic NPY gene expression was reduced in the mitoQ‐treated mice . Liver fat was markedly increased by HF feeding but did not differ between mitoQ and vehicle groups and, in contrast to our previous preventative study, there was no improvement in plasma alanine amino transferase or liver hydroperoxides. In summary, administration of mitoQ to already obese mice attenuated weight gain, but showed limited overall benefit.

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Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation

Cited by 35 publications

References 65 publications

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice

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