Functional roles of the neuropeptide PACAP in brain and pancreas.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide implicated in a broad variety of physiological processes. To assess PACAP's function in vivo, we recently generated PACAP knockout mice (PACAP(-/-)) and transgenic mice overexpressing PACAP specifically in the pancreas (PACAP-Tg). In PACAP(-/-) mice, we have demonstrated a marked phenotypic changes including a high early mortality rate, increased novelty-seeking behavior and abnormal explosive jumping in a novel environment, as well as reduced female fertility. In this paper, we reevaluated these phenotypes in terms of the genetic background of the mice. Genetic background appears to modulate critically the magnitude but not the general nature of the PACAP-null phenotype. In PACAP-Tg mice, we have recently demonstrated that enhanced glucose-induced insulin secretion with normal glucose tolerance, amelioration of streptozotocin-induced diabetes with increased beta-cell proliferation, and a trend towards an increase in total islet mass with age. Here we show that PACAP(-/-) mice exhibit significantly impaired glucose-induced insulin secretion but still have normal glucose tolerance. These observations suggest that PACAP may play important roles in and beyond the regulation of insulin release. Taken together, the mutant phenotypes revealed both expected and unexpected roles of PACAP in the brain and pancreatic functions.
Shintani
Norihito
N
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, 565-0871, Osaka, Japan.
Tomimoto
Shuhei
S
Hashimoto
Hitoshi
H
Kawaguchi
Chihiro
C
Baba
Akemichi
A
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000502:physiology*; D018390:Gene Targeting; D005947:Glucose / Q000494:pharmacology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D010179:Pancreas / Q000502:physiology*; D010641:Phenotype; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015398:Signal Transduction / Q000187:drug effects
C495402:Adcyap1 protein, mouse; D007328:Insulin; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D005947:Glucose