title: Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.
abstract: Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.forename: Derek
authors.initials: D
authors.lastname: Erion
authors.forename: Rudolph
authors.initials: R
authors.lastname: Beiler
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.forename: Alfonso
authors.initials: A
authors.lastname: Abizaid
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Zigman
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Savitt
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschoep
authors.forename: Robert H
authors.initials: RH
authors.lastname: Roth
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Gao
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D020267:MPTP Poisoning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D000214:Acyl Coenzyme A; D054439:Ghrelin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine