title: Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways.
abstract: Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by up-regulating BDNF.
authors.affiliation: Neuroscience Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australi.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
authors.forename: Yan-Chuan
authors.initials: YC
authors.lastname: Shi
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Aygul
authors.initials: A
authors.lastname: Aljanova
authors.forename: Zhou
authors.initials: Z
authors.lastname: Lin
authors.forename: Amy D
authors.initials: AD
authors.lastname: Nguyen
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000502:physiology; D007026:Hypothalamic Area, Lateral / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000502:physiology*; D000068797:Orexins; D010191:Pancreatic Polypeptide / Q000494:pharmacology / Q000502:physiology*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide