title: Temperature-sensitive phenotype in mice lacking pituitary adenylate cyclase-activating polypeptide.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved hormone. Targeted disruption of the PACAP gene has revealed a role for this peptide in lipid metabolism, carbohydrate metabolism, and the sympathetic response to insulin stress. We report here that PACAP null mice are temperature sensitive. When raised at 21 C, only 11% of the PACAP null mice survived past the first 2 wk after birth, but when raised at 24 C, most (76%) of the PACAP null mice survived. The question is the mechanism by which the absence of PACAP affects thermoregulation. Brown adipose tissue is the major site of adaptive thermogenesis in neonates and rodents. We show that PACAP null mice have brown adipocytes that differentiate normally and express two enzymes involved in thermogenesis, hormone-sensitive lipase and uncoupling protein 1. Likewise, levels of catecholamines in the adrenal medulla and plasma are normal in PACAP null mice raised at a lower temperature. In contrast, norepinephrine and its precursor dopamine extracted from brown adipose tissue are present at significantly lower levels in the PACAP null mice compared with controls. Also, PACAP null mice showed a greater loss of core body temperature compared with wild-type controls at 21 C. We conclude that under prolonged but mild cold stress, lack of PACAP results in inadequate heat production due to insufficient norepinephrine stimulation of brown adipose tissue.
authors.affiliation: Department of Biology, University of Victoria, British Columbia, Canada V8W 3N5.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Petra
authors.initials: P
authors.lastname: Vencová
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Sherwood
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D048429:Cell Size; D004298:Dopamine / Q000378:metabolism; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D024101:Mitochondrial Proteins; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D002787:Sterol Esterase / Q000378:metabolism; D013534:Survival; D013696:Temperature; D013697:Thermosensing / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: C495402:Adcyap1 protein, mouse; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D014446:Tyrosine 3-Monooxygenase; D002787:Sterol Esterase; D004298:Dopamine; D009638:Norepinephrine