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

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2015-11, Vol.309 (10), p.G816-G825
• Main Authors: Vu, John P, Goyal, Deepinder, Luong, Leon, Oh, Suwan, Sandhu, Ravneet, Norris, Joshua, Parsons, William, Pisegna, Joseph R, Germano, Patrizia M
• Format: Article
• Language: English
• Subjects: Animals; Appetite; Appetite - drug effects; Appetite Regulation - physiology; Digestive system; Dose-Response Relationship, Drug; Eating - drug effects; Feeding Behavior; Gastrointestinal Tract - metabolism; Ghrelin - antagonists & inhibitors; Ghrelin - blood; Glucagon-Like Peptide 1 - blood; Hormones; Hormones, Neurotransmitters, Growth Factors, Receptors, and Signaling; Injections, Intraperitoneal; Leptin - metabolism; Male; Mice; Models, Animal; Neurotransmitter Agents - administration & dosage; Neurotransmitter Agents - pharmacokinetics; Peptide YY - blood; Peptides; Physiology; Pituitary Adenylate Cyclase-Activating Polypeptide - administration & dosage; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacokinetics; Protein expression; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00190.2015

Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1-/-) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP1-38 or PACAP1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP1-38 administration in fasted WT mice. PACAP1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP1-38 injected into PAC1-/- mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1-/- mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1-/- mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.