title: PACAP is essential for the adaptive thermogenic response of brown adipose tissue to cold exposure.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widely distributed neuropeptide that acts as a neurotransmitter, neuromodulator, neurotropic factor, neuroprotectant, secretagogue, and neurohormone. Owing to its pleiotropic biological actions, knockout of Pacap (Adcyap1) has been shown to induce several abnormalities in mice such as impaired thermoregulation. However, the underlying physiological and molecular mechanisms remain unclear. A previous report has shown that cold-exposed Pacap null mice cannot supply appropriate levels of norepinephrine (NE) to brown adipocytes. Therefore, we hypothesized that exogenous NE would rescue the impaired thermogenic response of Pacap null mice during cold exposure. We compared the adaptive thermogenic capacity of Pacap(-/-) to Pacap(+/+) mice in response to NE when housed at room temperature (24 °C) and after a 3.5-week cold exposure (4 °C). Biochemical parameters, expression of thermogenic genes, and morphological properties of brown adipose tissue (BAT) and white adipose tissue (WAT) were also characterized. Results showed that there was a significant effect of temperature, but no effect of genotype, on the resting metabolic rate in conscious, unrestrained mice. However, the normal cold-induced increase in the basal metabolic rate and NE-induced increase in thermogenesis were severely blunted in cold-exposed Pacap(-/-) mice. These changes were associated with altered substrate utilization, reduced β3-adrenergic receptor (β3-Ar (Adrb3)) and hormone-sensitive lipase (Hsl (Lipe)) gene expression, and increased fibroblast growth factor 2 (Fgf2) gene expression in BAT. Interestingly, Pacap(-/-) mice had depleted WAT depots, associated with upregulated uncoupling protein 1 expression in inguinal WATs. These results suggest that the impairment of adaptive thermogenesis in Pacap null mice cannot be rescued by exogenous NE perhaps in part due to decreased β3-Ar-mediated BAT activation.
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
authors: Abdoulaye
authors: A
authors: Diané
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
authors: Nikolina
authors: N
authors: Nikolic
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
authors: Alexander P
authors: AP
authors: Rudecki
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
authors: Shannon M
authors: SM
authors: King
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
authors: Drew J
authors: DJ
authors: Bowie
authors: Northern Medical ProgramUniversity of Northern British Columbia, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9 Sarah.Gray@unbc.ca.
authors: Sarah L
authors: SL
authors: Gray
mesh_terms: D000064:Acclimatization / Q000235:genetics / Q000502:physiology; D052437:Adipocytes, Brown / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000033:anatomy & histology / Q000098:blood supply / Q000502:physiology*; D052436:Adipose Tissue, White / Q000033:anatomy & histology / Q000502:physiology; D000818:Animals; D001481:Basal Metabolism / Q000235:genetics / Q000502:physiology; D003081:Cold Climate; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D000071256:Uncoupling Protein 1
chemical_list: C495402:Adcyap1 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D022702:Receptors, Adrenergic, beta-3; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D016222:Fibroblast Growth Factor 2; D002787:Sterol Esterase
keywords: PACAP; cold; gene expression; mice; thermogenesis