Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus

Shi, Zhigang; Pelletier, Nicole E; Wong, Jennifer; Li, Baoxin; Sdrulla, Andrei D.; Madden, Christopher J.; Marks, Daniel L.; Brooks, Virginia L.

doi:10.7554/elife.55357

Cited by 39 publications

(32 citation statements)

References 98 publications

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“…Importantly, however, most studies investigating baroreflex regulation in the context of obesity were performed in species other than mice, such as in humans ( Grassi et al., 1998 ; Skrapari et al., 2007 ), dogs ( Lohmeier et al., 2016 ), and rats ( McCully et al., 2012 ), or in obese monogenic mice critically lacking leptin ( Hilzendeger et al., 2010 ) or leptin receptors ( Goncalves et al., 2009 ). In light of leptin’s prominent role in enhancing the baroreceptor reflex ( Li et al., 2013 ; Shi et al., 2020 ), and the fact that endogenous leptin action is retained in DIO at least in mice ( Ottaway et al., 2015 ), further studies are required to elucidate if differences in leptin sensitivity are responsible for the enhanced baroreflex gain we observed in DIO mice.…”

Section: Discussionmentioning

confidence: 99%

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

et al. 2021

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Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

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Section: Discussionmentioning

confidence: 99%

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

et al. 2021

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“…The brains were removed, post‐fixed for 6 hours and sectioned. Combined RNAScope (ACDBio, San Francisco, CA) in situ hybridisation for Npyr1 and immunohistochemistry for mCherry were then conducted as described previously 13 . As shown in Figure 1, the vast majority of mCherry neurones expressed NPY1R mRNA.…”

Section: Methodsmentioning

confidence: 99%

“…Rats were anaesthetised with isoflurane and prepared for DMH and PVN nanoinjections, and for measurements of BAT SNA, BAT T, mean and pulsatile arterial pressure (MAP and AP), and heart rate (HR) as described previously 13‐15 . When surgery was completed, rats were transitioned to α‐chloralose anaesthesia (Sigma, St Louis, MO, USA; 50 mg kg ‐1 loading dose followed by 25 mg kg ‐1 h ‐1 continuous infusion for the duration of the experiment) at the same time as slowing withdrawing the isoflurane over 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

Neuropeptide Y suppresses thermogenic and cardiovascular sympathetic nerve activity via Y1 receptors in the paraventricular nucleus and dorsomedial hypothalamus

Shi

Bonillas

Wong

et al. 2021

J Neuroendocrinology

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In hungry animals, neuropeptide Y (NPY) neurones in the arcuate nucleus (ArcN) are activated to suppress energy expenditure, in part by decreasing brown adipose tissue sympathetic nerve activity (BAT SNA); however, the NPY receptor subtype and brain neurocircuitry are unclear. In the present study, we investigated the inhibition of BAT SNA by exogenous and endogenous NPY via binding to Y1 receptors (NPY1R) in the hypothalamic paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH), in anaesthetised male rats. Downstream projections of PVN/DMH NPY1R‐expressing neurones were identified using male Npy1r‐cre mice and localised unilateral DMH or PVN injections of an adeno‐associated virus, which allows for the cre‐dependent expression of a fluorescent protein (mCherry) in the cell bodies, axon fibres and nerve terminals of NPY1R‐containing neurones. Nanoinjections of NPY into the DMH of cooled rats decreased BAT SNA, as well as mean arterial pressure (MAP) and heart rate (HR), and these responses were reversed by subsequent injection of the selective NPY1R antagonist, BIBO3304. In warmed rats, with little to no BAT SNA, bilateral nanoinjections of BIBO3304 into the DMH or PVN increased BAT SNA, MAP and HR. DMH NPY1R‐expressing neurones projected heavily to the raphe pallidus (RPa), which houses BAT presympathetic neurones, as well as the PVN. In anaesthetised mice, DMH BIBO3304 increased splanchnic SNA, MAP and HR, all of which were reversed by nonselective blockade of the PVN with muscimol, suggesting that DMH‐to‐PVN connections are involved in this DMH BIBO3304 disinhibition. PVN Y1R expressing neurones also projected to the RPa, as well as to the nucleus tractus solitarius. We conclude that NPY tonically released in the DMH and PVN suppresses BAT SNA, MAP and HR via Y1R. Downstream neuropathways for BAT SNA may utilise direct projections to the RPa. Release of tonic NPY inhibition of BAT SNA may contribute to feeding‐ and diet‐induced thermogenesis.

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“… 38 , 39 In the central neural network, RAS components, inflammatory factors and leptin act on these structures to alter neural processing and storage information to establish a new level of sympathetic nervous system basal activity and reactivity to stressors, such as seen with obesity‐related hypertension. 16 , 19 , 32 , 40 To explore the central mechanisms underlying maternal hypertension sensitization of postweaning HFD‐induced increase in BP, we determined the pressor effects of intracerebroventricular application of angiotensin II, TNF‐α, or leptin in offspring. We found that although LFD‐fed offspring of hypertensive dam had a normal baseline BP, they exhibited increased pressor responses to intracerebroventricular angiotensin II and to TNF‐α.…”

Section: Discussionmentioning

confidence: 99%

Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

Xue

Beltz

et al. 2021

JAHA

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Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II–induced hypertension in rats sensitizes postweaning high‐fat diet (HFD)‐elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low‐lard‐fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable. However, HFD feeding significantly increased mean arterial pressure in offspring of normotensive and hypertensive dams, but the elevated mean arterial pressure induced by HFD was greater in offspring of hypertensive dams, which was accompanied by greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin II or leptin. HFD feeding also produced comparable elevations in cardiac sympathetic activity and plasma levels of angiotensin II, interleukin‐6, and leptin in offspring of normotensive and hypertensive dams. Reverse transcriptase polymerase chain reaction analyses in key forebrain regions implicated in the control of sympathetic tone and blood pressure indicated that HFD feeding led to greater increases in mRNA expression of leptin, several components of the renin‐angiotensin system and proinflammatory cytokines in offspring of hypertensive dams when compared with offspring of normotensive dams. Conclusions The results indicate that maternal hypertension sensitized male adult offspring to HFD‐induced hypertension. Increased expression of renin‐angiotensin system components and proinflammatory cytokines, elevated brain reactivity to pressor stimuli, and augmented sympathetic drive to the cardiovascular system likely contributed.

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Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus

Cited by 39 publications

References 98 publications

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

Neuropeptide Y suppresses thermogenic and cardiovascular sympathetic nerve activity via Y1 receptors in the paraventricular nucleus and dorsomedial hypothalamus

Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

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