Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide which is involved in a variety physiological function. Regarding the appetite control, there are several reports that intracerebroventricular (ICV) injection of PACAP to mice reduced food intake (Resch et al, 2011, 2013, 2014). On the other hand, food intake is decreased in PACAP knockout (KO) mice (Nakata et al, 2004). Thus, there is some discrepancy in the functional role of PACAP in energy homeostasis including appetite control. Since the mechanism how PACAP regulates appetite remains unknown, we attempted to elucidate how PACAP is involved in the regulation of appetite in terms of the relationship with other neuropeptides regulating appetite.To address this issue, we assessed the expression of several neuropeptide which is involved in appetite control in PACAP knockout (KO) mice, and by administration of PACAP antagonist, PACAP[6-38] which is specific for PAC1R and VPAC2R. At first, we confirmed that nocturnal and daily food intake of PACAP KO mice was significantly lower than those of wild-type (WT) mice. Then, we observed that in food consumption at 4, 8, or 24 hours of refeeding after fasting for 2 days, the food intake at 8 hours of the refeeding was significantly lower in PACAP KO mice than in the WT mice, that is, PACAP KO mice showed a decrease in food intake in the fasting/refeeding paradigm. On the other hand, PACAP mRNA level was increased significantly by fasting in the whole hypothalamus of WT mice. The ICV administration of a PACAP antagonist PACAP[6-38] (1 nmol) reduced the diurnal food intake of WT mice after 1, 2, 4 and, 24 hours of injection. Furthermore we also observed that the expression level of agouti-related peptide (AgRP) was decreased in PACAP KO mice but that of proopiomelanocortin (POMC) was increased in the hypothalamus of PACAP KO mice after refeeding for 4 hours. On the other hand, the expression of AgRP was down-regulated by the injection of PACAP[6-38] at 4 hours after refeeding in WT mice. Taken together, our study demonstrated that food intake in mice was enhanced by the endogenous PACAP not only in daily but also in fasting-refeeding paradigms via the modulation of neuropeptides AgRP and/or POMC in the mouse hypothalamus, indicating endogenous PACAP might upregulate appetite in concert with other neuropeptides controlling appetite.