PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin.
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.
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California;
John P
JP
Vu
Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California;
Deepinder
D
Goyal
Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, California;
Leon
L
Luong
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California;
Suwan
S
Oh
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California;
Ravneet
R
Sandhu
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California;
Joshua
J
Norris
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, California;
William
W
Parsons
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, California; Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; CURE/Digestive Diseases Research Center, Department of Medicine, University of California, Los Angeles, California; and.
Joseph R
JR
Pisegna
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; CURE/Digestive Diseases Research Center, Department of Medicine, University of California, Los Angeles, California; and Division of Pulmonary and Critical Care, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California pgermano@ucla.edu.
Patrizia M
PM
Germano
D000818:Animals; D001066:Appetite / Q000187:drug effects; D001069:Appetite Regulation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005247:Feeding Behavior; D041981:Gastrointestinal Tract / Q000378:metabolism; D054439:Ghrelin / Q000037:antagonists & inhibitors / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007274:Injections, Intraperitoneal; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019894:Peptide YY / Q000097:blood; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000493:pharmacokinetics; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism*
D054439:Ghrelin; D020738:Leptin; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1
GLP-1; PAC1 receptor; appetite; ghrelin; leptin; pituitary adenylate cyclase-activating peptide