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

Abstract

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...

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

“…The results collectively suggest a role for the CeA PACAP/PAC1 receptor system in the regulation of appetite and energy homeostasis. PACAP microinfused into the CeA of non-restricted rats dose-dependently reduced food intake and body weight gain at doses very similar to those that elicit hypophagia at hypothalamic sites and with a similar duration of action (Resch et al, 2011;Resch et al, 2013). On the other hand, PACAP microinfused into the closely located BlA had no effect on either parameter, confirming specificity of action.…”

“…The hypophagia produced by PACAP administered within the hypothalamus is abolished by PAC1 antagonism, whereas pretreatment with VPAC antagonist has no effect (Mounien et al, 2009;Resch et al, 2013). These data, together with the observation that VIP does not reduce food intake (Mounien et al, 2009), strongly suggest the exclusive involvement of PAC1 receptors in the regulation of food intake.…”

“…We chose to use an FR1 schedule of reinforcement to reproduce in the operant boxes conditions that closely resembled those in the home cage (ad libitum consumption), which require a very low effort; the microstructure analysis used in this study is a well-established procedure, which has been extensively employed to study meal pattern following pharmacological treatments (Zorrilla et al, 2005). Although direct comparisons are difficult to make given the different microstructure definitions, the anorectic mechanism of PACAP when microinfused into the CeA appears to be analogous to that resulting from PACAP microinfusion into the paraventricular, but not the VMH, nucleus of the hypothalamus (Resch et al, 2013). Interestingly, a similar modality of anorectic action has been shown for MC4R activation, as MC4R agonism reduces meal size but not meal frequency (Williams et al, 2002;Zheng et al, 2005).…”

“…PACAP and its receptor PAC1 are highly expressed in the hypothalamus as well as in various extra-hypothalamic regions including the CeA (Joo et al, 2004;Piggins et al, 1996). The PACAP/PAC1 system is believed to play a key role in the regulation of feeding and energy homeostasis (Dore et al, 2013;KochoSchellenberg et al, 2014;Mounien et al, 2009;Resch et al, 2013). Although induction of anorexia is a well-documented effect of PACAP, the central sites and the mechanism underlying this phenomenon are poorly understood.…”

PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin

“…The expression of both PACAP and its PAC1 receptor in the hypothalamus suggests that they play a crucial role in the central regulation of feeding behavior via the hypothalamic melanocortin system (39). The central physiological effects of PACAP are mediated through its PAC1 receptor, as confirmed by the use of the PAC1-specific antagonist PACAP 6 -38 , which blocks the inhibitory central effects of PACAP on food intake (37,39,44,45). Furthermore, these enhancing satiety effects were replicated by using the PAC1 receptor-specific agonist maxadilan (38), which was shown to significantly suppress food intake in mice (60).…”