Numerous studies have demonstrated that the hypothalamic ventromedial nuclei (VMN) regulate energy homeostasis by integrating and utilizing behavioral and metabolic mechanisms. The VMN heavily express pituitary adenylate cyclase-activating polypeptide (PACAP) type I receptors (PAC1R). Despite the receptor distribution, most PACAP experiments investigating affects on feeding have focused on intracerebroventricular administration or global knockout mice. To identify the specific contribution of PACAP signaling in the VMN, we injected PACAP directly into the VMN and measured feeding behavior and indices of energy expenditure. Following an acute injection of PACAP, nocturnal food intake was significantly reduced for 6 h after injections without evidence of malaise. In addition, PACAP-induced suppression of feeding also occurred following an overnight fast and could be blocked by a specific PAC1R antagonist. Metabolically, VMN-specific injections of PACAP significantly increased both core body temperature and spontaneous locomotor activity with a concurrent increase in brown adipose uncoupling protein 1 mRNA expression. To determine which signaling pathways were responsive to PACAP administration into the VMN, we measured mRNA expression of well-characterized hypothalamic neuropeptide regulators of feeding. One hour after PACAP administration, expression of pro-opiomelanocortin mRNA was significantly increased in the arcuate nuclei (ARC), with no changes in neuropeptide Y and agouti-related polypeptide mRNA levels. This suggests that PAC1R expressing VMN neurons projecting to pro-opiomelanocortin neurons contribute to hypophagia by involving melanocortin signaling. While the VMN also abundantly express PACAP protein, the present study demonstrates that PACAP input to the VMN can influence the control of energy homeostasis.

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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Several endogenous oscillators determine circadian rhythms. One, light-entrained, is in the suprachiasmatic nuclei (SCN), the others, food-entrained, are in unknown sites. To determine how the hypothalamic ventromedial nuclei (VMN) and feeding affect rhythms, we compared nocturnally active rats fed either ad libitum or for 2 hr/d during light [restricted feeding (RF)] and either with or without colchicine-induced disruption of VMN. We measured rhythms in temperature, locomotor activity, feeding, drinking, corticosterone, and the numbers of cells expressing c-Fos in light/dark in hypothalamic nuclei, the suprachiasmatic nuclei, and two major SCN targets, the subparaventricular zone (sPVNz) and paraventricular thalamus (pvTHAL). c-Fos cells were always light > dark in SCN, whereas the VMN and sPVNz lacked light/dark differences except after RF and RF plus VMN disruption, respectively. Controls fed ad libitum had high-amplitude rhythms and, generally, c-Fos cells dark > light. In RF controls, a c-Fos pattern dark > light occurred in VMN; generally, c-Fos cell numbers increased elsewhere maintaining dark > light. By contrast, levels of corticosterone peaked before food. In rats fed ad libitum, VMN with colchicine markedly reduced rhythm amplitudes, not phase. c-Fos patterns were abolished except in pvTHAL and SCN. In RF, VMN disruption blocked corticosterone and light/dark c-Fos patterns in all nuclei but produced a pattern in the sPVNz like SCN. We conclude that VMN amplify rhythmic output from the SCN, and the RF-induced rhythm in VMN enhances c-Fos activity driven by the SCN. The VMN may contain a food-entrained oscillator, and the sPVNz may integrate output from several oscillators.

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.