Insulin increases sympathetic nerve activity in part by suppression of tonic inhibitory neuropeptide Y inputs into the paraventricular nucleus in female rats

Cassaglia, Priscila A.; Shi, Zhigang; Brooks, Virginia L.

doi:10.1152/ajpregu.00054.2016

Cited by 25 publications

(38 citation statements)

References 18 publications

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“…Because the increase in LSNA evoked by insulin is mediated largely by POMC neurons and release of α‐MSH into the PVN (Cassaglia et al . ), these results also suggest that insulin does not activate ArcN POMC neurons normally in OP females.…”

Section: Resultssupporting

confidence: 54%

“…As expected (Cassaglia et al . ), subsequent PVN BIBO3304 nanoinjections did not increase LSNA in lean CON and OR rats (because insulin had inhibited NPY inputs). However, BIBO3304 increased LSNA in OP rats (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…) to suppress tonic sympathoinhibitory NPY inputs (Cassaglia et al . ) (Fig. ) and activate excitatory α‐MSH and glutamatergic inputs (Ward et al .…”

Section: Discussionmentioning

confidence: 99%

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Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y

Shi

Cassaglia

Pelletier

et al. 2019

The Journal of Physiology

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Key points Intracerebroventricular insulin increased sympathetic nerve activity (SNA) and baroreflex control of SNA and heart rate more dramatically in obese male rats; in obese females, the responses were abolished. In obese males, the enhanced lumbar SNA (LSNA) responses were associated with reduced tonic inhibition of LSNA by neuropeptide Y (NPY) in the PVN. However, PVN NPY injection decreased LSNA similarly in obesity prone/obesity resistant/control rats. Collectively, these results suggest that NPY inputs were decreased. In obese females, NPY inhibition in the PVN was maintained. Moreover, NPY neurons in the arcuate nucleus became resistant to the inhibitory effects of insulin. A high‐fat diet did not alter arcuate NPY neuronal InsR expression in males or females. Obesity‐induced ‘selective sensitization’ of the brain to the sympathoexcitatory effects of insulin and leptin may contribute to elevated basal SNA, and therefore hypertension development, in males with obesity. These data may explain in part why obesity increases SNA less in women compared to men. Abstract Obesity increases sympathetic nerve activity (SNA) in men but not women; however, the mechanisms are unknown. We investigated whether intracerebroventricular insulin infusion increases SNA more in obese male than female rats and if sex differences are mediated by changes in tonic inhibition of SNA by neuropeptide Y (NPY) in the paraventricular nucleus (PVN). When consuming a high‐fat diet, obesity prone (OP) rats accrued excess fat, whereas obesity resistant (OR) rats maintained adiposity as in rats eating a control (CON) diet. Insulin increased lumbar SNA (LSNA) similarly in CON/OR males and females under urethane anaesthesia. The LSNA response was magnified in OP males but abolished in OP females. In males, blockade of PVN NPY Y1 receptors with BIBO3304 increased LSNA in CON/OR rats but not OP rats. Yet, PVN nanoinjections of NPY decreased LSNA similarly between groups. Thus, tonic PVN NPY inhibition of LSNA may be lost in obese males as a result of a decrease in NPY inputs. By contrast, in females, PVN BIBO3304 increased LSNA similarly in OP, OR and CON rats. After insulin, PVN BIBO3304 failed to increase LSNA in CON/OR females but increased LSNA in OP females, suggesting that with obesity NPY neurons become resistant to the inhibitory effects of insulin. These sex differences were not associated with changes in arcuate NPY neuronal insulin receptor expression. Collectively, these data reveal a marked sex difference in the impact of obesity on the sympathoexcitatory actions of insulin and implicate sexually dimorphic changes in NPY inhibition of SNA in the PVN as one mechanism.

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Section: Resultssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 93%

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Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y

Shi

Cassaglia

Pelletier

et al. 2019

The Journal of Physiology

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“…Based on anatomical evidence that PVN presympathetic neurons are richly innervated by ArcN NPY fibers in mice ( Figure 2) and rats (4), the strong sympathoinhibitory effects of NPY in the PVN in mice (Figure 3) and rats (4), and indirect evidence in rats that ArcN NPY neurons inhibit SNA via a synapse in the PVN (5,7,8), we were surprised that blockade of PVN NPY1R only weakly reversed the effects of select ArcN NPY/AgRP neuronal activation. In sharp contrast, blockade of DMH NPY1R completely reversed these effects.…”

Section: Discussionmentioning

confidence: 99%

“…Indirect evidence implicates an NPY projection from the ArcN. More specifically, injections of leptin or insulin into the ArcN, or nonspecific activation of the ArcN, increase SNA in part via suppression of tonic NPY inhibition of PVN presympathetic neurons (5,7,8). However, whether the PVN NPY input that is suppressed by insulin and leptin originates directly from neurons in the ArcN has not been established.…”

Section: Introductionmentioning

confidence: 99%

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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Taurine Supplementation Reduces Renal Nerve Activity in Male Rats in which Renal Nerve Activity was Increased by a High Sugar Diet

Rakmanee

Kulthinee

Wyss

et al. 2017

Advances in Experimental Medicine and Biology

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This study tests the hypothesis that taurine supplementation reduces sugar-induced increases in renal sympathetic nerve activity related to renin release in adult male rats. After weaning, male rats were fed normal rat chow and drank water containing 5% glucose (CG) or water alone (CW) throughout the experiment. At 6-7 weeks of age, each group was supplemented with or without 3% taurine in drinking water until the end of experiment. At 7-8 weeks of age, blood chemistry and renal nerve activity were measured in anesthetized rats. Body weights slightly and significantly increased in CG compared to CW groups but were not significantly affected by taurine supplementation. Plasma electrolytes except bicarbonate, plasma creatinine, and blood urea nitrogen were not significantly different among the four groups. Mean arterial pressure significantly increased in both taurine treated groups compared to CW, while heart rates were not significantly different among the four groups. Further, all groups displayed similar renal nerve firing frequencies at rest and renal nerve responses to sodium nitroprusside and phenylephrine infusion. However, compared to CW group, CG significantly increased the power density of renin release-related frequency component, decreased that of sodium excretion-related frequency component, and decreased that of renal blood flow-related frequency component. Taurine supplementation completely abolished the effect of high sugar intake on renal sympathetic activity patterns. These data indicate that in adult male rats, high sugar intake alters the pattern but not firing frequency of sympathetic nerve activity to control renal function, and this effect can be improved by taurine supplementation.

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Insulin increases sympathetic nerve activity in part by suppression of tonic inhibitory neuropeptide Y inputs into the paraventricular nucleus in female rats

Cited by 25 publications

References 18 publications

Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y

Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Taurine Supplementation Reduces Renal Nerve Activity in Male Rats in which Renal Nerve Activity was Increased by a High Sugar Diet

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