Efferent projections of neuropeptide Y‐expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models

Lee, Shin J.; Kirigiti, Melissa A.; Lindsley, Sarah R.; Loche, Alberto; Madden, Christopher J.; Morrison, Shaun F.; Smith, M. Susan; Grove, Kevin L.

doi:10.1002/cne.23265

Cited by 47 publications

(47 citation statements)

References 97 publications

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“…The NPY inputs to the PVH come from the ARC, the DMH, and the VLM. Consistent with an NPY input from DMH augmenting the BAT sympathoinhibitory effect of PVH neurons, NPY neurons in DMH project to PVH, but not to rRPa or NTS (Lee et al, 2013) and knockdown of NPY in the compact DMH increased BAT UCP-1 expression and cold-evoked thermogenesis and stimulated “browning” in inguinal white adipose tissue (Chao et al, 2011). In contrast, activation of MC4-R, which are located in the vicinity of PVH neurons synaptically-connected to BAT (Song et al, 2008) (Fig.…”

Section: Hypothalamic Influences On Bat Thermogenesismentioning

confidence: 83%

Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

2014

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SUMMARY Thermogenesis, the production of heat energy, is the specific, neurally-regulated, metabolic function of brown adipose tissue (BAT) and contributes to the maintenance of body temperature during cold exposure and to the elevated core temperature during several behavioral states, including wakefulness, the acute phase response (fever), and stress. BAT energy expenditure requires metabolic fuel availability and contributes to energy balance. This review summarizes the functional organization and neurochemical influences within the CNS networks governing the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolically-driven alterations in BAT thermogenesis and energy expenditure that contribute to overall energy homeostasis.

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Section: Hypothalamic Influences On Bat Thermogenesismentioning

confidence: 83%

Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

2014

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“…The projections of NPY-containing DMH neurons are mostly limited to hypothalamic regions including the PVH (Lee et al, 2013). In the present study, NPY injection into the lateral ventricle, as well as into the PVH, strongly inhibited skin cooling-evoked BAT thermogenesis and tachycardia, and, independent of injection site, the inhibitory effects of NPY were completely reversed by inactivation of IRt/PCRt neurons.…”

Section: Discussionmentioning

confidence: 99%

Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication

et al. 2017

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SUMMARY Hypothalamic neuropeptide Y (NPY) elicits hunger responses to increase the chances of surviving starvation: an inhibition of metabolism and an increase in feeding. Here we elucidate a key central circuit mechanism through which hypothalamic NPY signals drive these hunger responses. GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) of the medulla oblongata, which are activated by NPY-triggered neural signaling from the hypothalamus, potentially through the nucleus tractus solitarius, mediate the NPY-induced inhibition of metabolic thermogenesis in brown adipose tissue (BAT) via their innervation of BAT sympathetic premotor neurons. Intriguingly, the GABAergic IRt/PCRt neurons innervating the BAT sympathetic premotor region also innervate the masticatory motor region, and stimulation of the IRt/PCRt elicits mastication and increases feeding as well as inhibits BAT thermogenesis. These results indicate that GABAergic IRt/PCRt neurons mediate hypothalamus-derived hunger signaling by coordinating both autonomic and feeding motor systems to reduce energy expenditure and to promote feeding.

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“…One week after the surgery, the mice received another stereotaxic injection of Alexa Fluor 488-CtB (1 mg/ml, 30 nl, Life Technologies, Invitrogen) into the RVLM (coordinates: 1.5 to 1.6 mm caudal to lambda, 0.9 to 1.1 mm lateral to midline, 4.9 to 5.1 mm ventral to dura) using a pressure injection system. One week later, the animals were perfused with 4% paraformaldehyde, and the brains were sectioned at 30 μm on a (Supplemental Figure 10), a well-described projection target in both rats and mice (11,47). Moreover, only a modest number of DMH neurons that were retrogradely labeled from the RVLM were closely associated with ArcN NPY neurons traced with a synaptophysin mCherry label (Figure 2), although we cannot discount the possible inhibitory influence of NPY on DMH-to-RVLM neurons via volume transmission (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…However, whether the PVN NPY input that is suppressed by insulin and leptin originates directly from neurons in the ArcN has not been established. In addition to the ArcN, (9), NPY projections from the brainstem (10) and, under some circumstances, the dorsomedial hypothalamus (DMH) (11) are alternative candidates. Moreover, whether other ArcN NPY projections influence the sympathetic nervous system or arterial pressure (AP) has not been investigated.…”

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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Efferent projections of neuropeptide Y‐expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models

Cited by 47 publications

References 97 publications

Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

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