Purpose: PACAP is a pituitary and gastrointestinal neuropeptide, which binds with high affinity to the PAC1 receptor and has physiological effects on endocrine and exocrine pancreatic secretions. We previously reported that PAC1 null mice exhibit an obese phenotype compared to wild type (WT) mice. We also demonstrated that PACAP injected intra-peritoneally inhibits appetite in WT mice. This led us to hypothesize that PACAP and PAC1 may regulate the secretion of key gastrointestinal hormones that regulate appetite. Methods: A total of 32 age- and weight-matched PAC1 null (n=16) and WT (n=16) male C57BL/6 mice were included in the study. After 16 hours of overnight fast in a controlled environment, 8/16 randomly selected mice from each of the two groups were subjected to fasting blood draw. The other half in both the groups (8/16) were allowed ad-libitum feeding and blood sampling was conducted 30-60 minutes later for a prandial sample. Levels of active-ghrelin (a-ghrelin), glucagon like peptide-1 (GLP-1), glucagon, insulin, amylin, pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY) were determined using Luminex x-MAP technology. Results: The median post-prandial levels of a-ghrelin were significantly different in the two groups; 363 (IQR 185.5-607.5) in PAC1 null vs. 7.9 (IQR 1.9-74) pg/mL (p=0.003) in WT mice. There was no difference in median fasting a-ghrelin levels in PAC1 null 552 (IQR 402-924) as compared to WT mice 381 (IQR 299-602) pg/mL. As expected, PAC1 null mice had significantly lower median fasting [58.1 (IQR, 26.5-104.5) vs. 288 (IQR 256-698) pg/mL (p<0.001) and prandial [135.5 (IQR 93.4-210) vs. 2368.5 (IQR 2178.5-3665.5) pg/mL (p<0.001) insulin, and lower median fasting [7.2 (IQR 5.8-12.6) vs. 13.4 (IQR 13.4-35.2) pg/mL (p=0.03) and prandial [12.2 (IQR 6.1-23.6) vs. 29.9 (IQR 13.4-57.3) pg/mL (p=0.03) levels of glucagon than WT mice. No difference was seen in median PYY levels among PAC1 null as compared to WT mice in both fasting 76.9 (IQR 44.4-124.5) vs. 61.3 (13.7-108) pg/mL and feeding state 76.8 (IQR 49.6-109.7) vs. 94.8 (IQR 62.5-181) pg/mL. There was no significant difference in the levels of GLP-1, PP, and amylin between PAC1 null and WT mice. Conclusion: In mice lacking PAC1 receptor, levels of active ghrelin remained elevated in the post-prandial state in contrast to their wild type counterparts which demonstrated a significant fall in their ghrelin levels after feeding. PACAP plays a key role in appetite regulation and energy homeostasis by suppressing the release of major orexigenic hormone ghrelin. PAC-1 receptor agonist may act as potential therapeutic agent for appetite down-regulation in overweight individuals which merits further investigations.