PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling

Hawke, Zoe; Ivanov, Tina R.; Bechtold, David A.; Dhillon, Harveen; Lowell, Brad B.; Luckman, Simon M.

doi:10.1523/jneurosci.1526-09.2009

Cited by 93 publications

(152 citation statements)

References 62 publications

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“…Importantly, site-specific hypothalamic injections do not cause sedation or aversive effects (50) that can sometimes arise following exogenous peptide administration. Although there are multiple PACAP receptor subtypes expressed in the hypothalamus, the reduction in feeding behavior appears to be mediated primarily by the PAC1R subtype, which is in agreement with prior feeding studies (27,40,50). Specifically, in both the PVN and VMN, the effects of PACAP could be blocked by the VPAC2R/PAC1R antagonist PACAP(6 -38) but not by the VPAC1R/VPAC2R antagonist VIP (6 -28).…”

Section: Discussionsupporting

confidence: 83%

“…Expression of multiple PACAP receptor subtypes in the hypothalamus suggests that PACAP is a multifunctional neuropeptide signal that contributes to several behavioral and physiological systems. The feasibility of this concept is supported by reports linking PACAP to stress (51), anxiety (22), feeding (27,40,50), and glucose mobilization (60), all systems that may work synergistically and converge on PACAP-enriched anatomic areas such as the hypothalamus and amygdala (25).…”

Section: Discussionmentioning

confidence: 96%

“…For studies involving antagonism of PACAP receptors, rats were bilaterally pretreated with saline, PACAP(6 -38) (500 pmol/0.25 l per side, Anaspec) or VIP(6 -28) (500 pmol/0.25 l per side, Bachem). PACAP(6 -38) is a widely used PAC1R antagonist; however, it also has antagonistic properties at the VPAC2R (19,27,40,52), and VIP(6 -28) is reported to be a potent nonselective VPAC receptor antagonist (16,38,54) shown to be effective in the hypothalamus (28). Five minutes later, rats received a second bilateral injection of either saline or 50 pmol PACAP followed by subsequent physiological and behavioral measurements.…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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Projections from the subparaventricular zone define four channels of output from the circadian timing system

Vujović

Gooley

Jhou

et al. 2015

J of Comparative Neurology

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The subparaventricular zone of the hypothalamus (SPZ) is the main efferent target of neural projections from the suprachiasmatic nucleus (SCN) and an important relay for the circadian timing system. Although the SPZ is fairly homogeneous cytoarchitecturally and neurochemically, it has been divided into distinct functional and connectional subdivisions. The dorsal subdivision of the SPZ (dSPZ) plays an important role in relaying signals from the SCN controlling body temperature rhythms while the ventral subdivision (vSPZ) is critical for rhythms of sleep and locomotor activity (Lu et al., 2001). On the other hand, the medial part of the SPZ receives input mainly from the dorsomedial SCN, whereas the lateral SPZ receives input from the ventrolateral SCN and the retinohypothalamic tract (Leak and Moore, 2001). We have therefore investigated whether there are corresponding differences in efferent outputs from these four quadrants of the SPZ (dorsolateral, ventrolateral, dorsomedial and ventromedial) by a combination of anterograde and retrograde tracing. We found that while all four subdivisions of the SPZ share a similar backbone of major projection pathways to the septal region, thalamus, hypothalamus, and brainstem, each segment of the SPZ has a specific set of targets where its projections dominate. Furthermore, we observed intra-SPZ projections of varying densities between the four subdivisions. Taken together, this pattern of organization suggests that the circadian timing system may have several parallel neural outflow pathways that provide a road map for understanding how they subserve different functions.

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CNS Targets of Adipokines

Beall

Hanna

Ellacott

2017

Comprehensive Physiology

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Our understanding of adipose tissue as an endocrine organ has been transformed over the last 20 years. During this time, a number of adipocyte-derived factors or adipokines have been identified. This article will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted. © 2017 American Physiological Society. Compr Physiol 7:1359-1406, 2017.

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PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling

Cited by 93 publications

References 62 publications

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

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

Projections from the subparaventricular zone define four channels of output from the circadian timing system

CNS Targets of Adipokines

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