title: Pituitary adenylate cyclase-activating polypeptide stimulates glucose production via the hepatic sympathetic innervation in rats.
abstract: OBJECTIVE
  The unraveling of the elaborate brain networks that control glucose metabolism presents one of the current challenges in diabetes research. Within the central nervous system, the hypothalamus is regarded as the key brain area to regulate energy homeostasis. The aim of the present study was to investigate the hypothalamic mechanism involved in the hyperglycemic effects of the neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP).
  
  
  METHODS
  Endogenous glucose production (EGP) was determined during intracerebroventricular infusions of PACAP-38, vasoactive intestinal peptide (VIP), or their receptor agonists. The specificity of their receptors was examined by coinfusions of receptor antagonists. The possible neuronal pathway involved was investigated by 1) local injections in hypothalamic nuclei, 2) retrograde neuronal tracing from the thoracic spinal cord to hypothalamic preautonomic neurons together with Fos immunoreactivity, and 3) specific hepatic sympathetic or parasympathetic denervation to block the autonomic neuronal input to liver.
  
  
  RESULTS
  Intracerebroventricular infusion of PACAP-38 increased EGP to a similar extent as a VIP/PACAP-2 (VPAC2) receptor agonist, and intracerebroventricular administration of VIP had significantly less influence on EGP. The PACAP-38 induced increase of EGP was significantly suppressed by preinfusion of a VPAC2 but not a PAC1 receptor antagonist, as well as by hepatic sympathetic but not parasympathetic denervation. In the hypothalamus, Fos immunoreactivity induced by PACAP-38 was colocalized within autonomic neurons in paraventricular nuclei projecting to preganglionic sympathetic neurons in the spinal cord. Local infusion of PACAP-38 directly into the PVN induced a significant increase of EGP.
  
  
  CONCLUSIONS
  This study demonstrates that PACAP-38 signaling via sympathetic preautonomic neurons located in the paraventricular nucleus is an important component in the hypothalamic control of hepatic glucose production.
authors.affiliation: Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. c.yi@nin.knaw.nl
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Mariette T
authors.initials: MT
authors.lastname: Ackermans
authors.forename: Anneke
authors.initials: A
authors.lastname: Alkemade
authors.forename: Ewout
authors.initials: E
authors.lastname: Foppen
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Mireille J
authors.initials: MJ
authors.lastname: Serlie
authors.forename: Ruud M
authors.initials: RM
authors.lastname: Buijs
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Andries
authors.initials: A
authors.lastname: Kalsbeek
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D005947:Glucose / Q000096:biosynthesis*; D006706:Homeostasis; D007276:Injections, Intraventricular; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D008297:Male; D056325:Neuronal Tract-Tracers; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D056325:Neuronal Tract-Tracers; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016760:Proto-Oncogene Proteins c-fos; D014660:Vasoactive Intestinal Peptide; D005947:Glucose