Leptin-Receptor-Expressing Neurons in the Dorsomedial Hypothalamus and Median Preoptic Area Regulate Sympathetic Brown Adipose Tissue Circuits

Zhang, Yan; Kerman, Ilan A.; Laque, Amanda; Nguyen, Phillip; Faouzi, Miro; Louis, Gwendolyn W.; Jones, Justin C.; Rhodes, C. G.; Münzberg, Heike

doi:10.1523/jneurosci.3223-10.2011

Cited by 220 publications

(250 citation statements)

References 67 publications

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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%

“…Prior neuroanatomical studies in the rat (44)(45)(46) and mouse (47) reveal that the DMH heavily innervates many preautonomic regions, particularly in the forebrain. A very dense projection is to the caudal parvocellular PVN, a hypothalamic subnucleus that projects to the RVLM and the spinal cord (44)(45)(46)(47). The median POA, the perifornical area, and the PAG are also major projection targets (45,47).…”

Section: Discussionmentioning

confidence: 99%

“…A very dense projection is to the caudal parvocellular PVN, a hypothalamic subnucleus that projects to the RVLM and the spinal cord (44)(45)(46)(47). The median POA, the perifornical area, and the PAG are also major projection targets (45,47). Future studies are required to specifically delineate the neuropathways involved.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Shi¹,

Madden²,

Brooks³

2017

Journal of Clinical Investigation

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“…Whereas transynaptic retrograde tracing studies from the iBAT often fail to detect VMN neurons (5,46), there is ample evidence supporting VMN activation of BAT thermogenesis, including both VMN-specific microinjection and genetic studies (2,30,49,50). It is feasible that the VMN exerts its influences over hypothalamic structures that are labeled by transynaptic tracers from BAT such as the medial preoptic area, dorsomedial nuclei, or lateral hypothalamus (46,61), allowing for indirect and downstream effects on BAT thermogenesis that are not observed in more proximal polysynaptic tracing experiments. Future studies are needed to reconcile the discrepancy between the anatomical and functional studies regarding VMN-mediated BAT thermogenesis.…”

Section: Discussionmentioning

confidence: 99%

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Resch

Maunze

Gerhardt

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Resch JM, Maunze B, Gerhardt AK, Magnuson SK, Phillips KA, Choi S. Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism. Am J Physiol Endocrinol Metab 305: E1452-E1463, 2013. First published October 22, 2013; doi:10.1152/ajpendo.00293.2013.-Numerous studies have demonstrated that both the hypothalamic paraventricular nuclei (PVN) and ventromedial nuclei (VMN) regulate energy homeostasis through behavioral and metabolic mechanisms. Receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are abundantly expressed in these nuclei, suggesting PACAP may be critical for the regulation of feeding behavior and body weight. To characterize the unique behavioral and physiological responses attributed to select hypothalamic cell groups, PACAP was site-specifically injected into the PVN or VMN. Overall food intake was significantly reduced by PACAP at both sites; however, meal pattern analysis revealed that only injections into the PVN produced significant reductions in meal size, duration, and total time spent eating. PACAP-mediated hypophagia in both the PVN and VMN was abolished by PAC1R antagonism, whereas pretreatment with a VPACR antagonist had no effect. PACAP injections into the VMN produced unique changes in metabolic parameters, including significant increases in core body temperature and spontaneous locomotor activity that was PAC1R dependent whereas, PVN injections of PACAP had no effect. Finally, PACAP-containing afferents were identified using the neuronal tracer cholera toxin subunit B (CTB) injected unilaterally into the PVN or VMN. CTB signal from PVN injections was colocalized with PACAP mRNA in the medial anterior bed nucleus of the stria terminalis, VMN, and lateral parabrachial nucleus (LPB), whereas CTB signal from VMN injections was highly colocalized with PACAP mRNA in the medial amygdala and LPB. These brain regions are known to influence energy homeostasis perhaps, in part, through PACAP projections to the PVN and VMN.feeding; activity; temperature; hypothalamus; rat PITUITARY ADENYLATE CYCLASE-ACTIVATING polypeptide (PACAP) is a key regulator of several hypothalamic systems, including stress (1), osmoregulation (17), thermoregulation (21), and body weight (27). PACAP was first discovered to influence energy homeostasis through inhibition of feeding in mice following a single intracerebroventricular (icv) injection of the peptide (39). These results combined with reports of dietspecific alterations of PACAP mRNA expression in the hypothalamic ventromedial nuclei (VMN) suggest that PACAP is responsive to nutritional status and directly tied to metabolic systems linked to energy expenditure (27,40). In addition to reducing food intake, icv administration of PACAP modulates autonomic nerve activity (55) as well as hepatic glucose production (60). As a ligand, PACAP binds to three different G protein-coupled receptors, the PAC1 receptor (PAC1R), and the receptors originally discovered as targets...

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“…Recently, some of the other adipokines (visfatin, leptin, and IGF) were shown to produce hyperthermia after administration into the CNS. 12,[38][39][40][41] In addition, because high-fat feeding alters the FA content in tissues and body fluids, the biosynthesis and secretion of lipid mediators may be altered. These have bioactive effects mediated through receptors or binding proteins, and some lipids are known to activate enzymes.…”

Section: Discussionmentioning

confidence: 99%

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

Tsushima

Yamada

Miyazawa

et al. 2014

Biological & Pharmaceutical Bulletin

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We investigated whether body temperature (BT) regulatory mechanisms are influenced by dietary fatty acids (FA). Male Wistar rats were fed a high-fat diet containing fish oil (HFD), soybean oil (HSD) or lard (HLD). At the 20-week intervention, the BT of the HSD and HLD groups were lower than that of the normal diet (ND) group in the light and dark periods. The intracerebroventricular injections of interleukin-1β and bombesin in the HSD group induced greater hyperthermia and weaker hypothermia, respectively, than in the ND group. The HSD differentially affected BT under both physiological and pharmacological conditions. In the hypothalamus, the ratio of n-6/n-3 FAs was higher in the HSD group compared with the ND group. DNA microarrays revealed increased expression of thyroid-stimulating hormone β-subunit, and decreased expression of several genes in the hypothalamus of the HSD group compared with the ND group. The HSD feeding increased several adipokine concentrations in the plasma. However, there were no adipokines or gene expressions that changed in only the HSD and HLD groups showing significant hypothermia under the physiological condition. These findings suggested that long-term HSD intake produces abnormal BT regulation. It is less likely that adipokines or proteins/peptides are involved in abnormal BT regulation under the physiological conditions after HSD feeding.Key words body temperature; hypothalamus; high-fat diet; interleukin (IL)-1β; bombesinWe now obtain more energy from fat and glucose than ever before. These changes have induced hyperlipidemia and adipocyte hypertrophy, resulting in the risk of cardiovascular diseases, diabetes mellitus and obesity. From this point of view, there are many reports on lipid and/or glucose metabolisms during high-fat diet feeding in living animals.

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Leptin-Receptor-Expressing Neurons in the Dorsomedial Hypothalamus and Median Preoptic Area Regulate Sympathetic Brown Adipose Tissue Circuits

Cited by 220 publications

References 67 publications

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

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