Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism

Zane B. Andrews, Derek Erion, Rudolph Beiler, Zhong Wu Liu, Alfonso Abizaid, Jeffrey Zigman, John D. Elsworth, Joseph M Savitt, Richard DiMarchi, Matthias Tschoep, Robert H. Roth, Xiao Bing Gao, Tamas L. Horvath

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)14057-14065
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number45
DOIs
StatePublished - Nov 11 2009

Fingerprint

Ghrelin Receptor
Ghrelin
Dopamine
Corpus Striatum
Parkinson Disease
Dopaminergic Neurons
Adiposity
Tyrosine 3-Monooxygenase
Appetite
Uncoupling Protein 2
Reward
Hypothalamus
Oxidation-Reduction
Reactive Oxygen Species
Respiration
Therapeutics
Obesity
Eating
Body Weight
Maintenance

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Andrews, Z. B., Erion, D., Beiler, R., Liu, Z. W., Abizaid, A., Zigman, J., ... Horvath, T. L. (2009). Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. Journal of Neuroscience, 29(45), 14057-14065. https://doi.org/10.1523/JNEUROSCI.3890-09.2009

Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. / Andrews, Zane B.; Erion, Derek; Beiler, Rudolph; Liu, Zhong Wu; Abizaid, Alfonso; Zigman, Jeffrey; Elsworth, John D.; Savitt, Joseph M; DiMarchi, Richard; Tschoep, Matthias; Roth, Robert H.; Gao, Xiao Bing; Horvath, Tamas L.

In: Journal of Neuroscience, Vol. 29, No. 45, 11.11.2009, p. 14057-14065.

Research output: Contribution to journalArticle

Andrews, ZB, Erion, D, Beiler, R, Liu, ZW, Abizaid, A, Zigman, J, Elsworth, JD, Savitt, JM, DiMarchi, R, Tschoep, M, Roth, RH, Gao, XB & Horvath, TL 2009, 'Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism', Journal of Neuroscience, vol. 29, no. 45, pp. 14057-14065. https://doi.org/10.1523/JNEUROSCI.3890-09.2009
Andrews, Zane B. ; Erion, Derek ; Beiler, Rudolph ; Liu, Zhong Wu ; Abizaid, Alfonso ; Zigman, Jeffrey ; Elsworth, John D. ; Savitt, Joseph M ; DiMarchi, Richard ; Tschoep, Matthias ; Roth, Robert H. ; Gao, Xiao Bing ; Horvath, Tamas L. / Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 45. pp. 14057-14065.
@article{613743dea11447b5966c7f90196a0ce3,
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.",
author = "Andrews, {Zane B.} and Derek Erion and Rudolph Beiler and Liu, {Zhong Wu} and Alfonso Abizaid and Jeffrey Zigman and Elsworth, {John D.} and Savitt, {Joseph M} and Richard DiMarchi and Matthias Tschoep and Roth, {Robert H.} and Gao, {Xiao Bing} and Horvath, {Tamas L.}",
year = "2009",
month = "11",
day = "11",
doi = "10.1523/JNEUROSCI.3890-09.2009",
language = "English (US)",
volume = "29",
pages = "14057--14065",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "45",

}

TY - JOUR

T1 - Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism

AU - Andrews, Zane B.

AU - Erion, Derek

AU - Beiler, Rudolph

AU - Liu, Zhong Wu

AU - Abizaid, Alfonso

AU - Zigman, Jeffrey

AU - Elsworth, John D.

AU - Savitt, Joseph M

AU - DiMarchi, Richard

AU - Tschoep, Matthias

AU - Roth, Robert H.

AU - Gao, Xiao Bing

AU - Horvath, Tamas L.

PY - 2009/11/11

Y1 - 2009/11/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70449673061&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70449673061&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3890-09.2009

DO - 10.1523/JNEUROSCI.3890-09.2009

M3 - Article

VL - 29

SP - 14057

EP - 14065

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 45

ER -