UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals

Zane B. Andrews; Zhong Wu Liu; Nicholas Walllingford; Derek M. Erion; Erzsebet Borok; Jeffery M. Friedman; Matthias H. Tschöp; Marya Shanabrough; Gary Cline; Gerald I. Shulman; Anna Coppola; Xiao Bing Gao; Tamas L. Horvath; Sabrina Diano

doi:10.1038/nature07181

UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals

Zane B. Andrews, Zhong Wu Liu, Nicholas Walllingford, Derek M. Erion, Erzsebet Borok, Jeffery M. Friedman, Matthias H. Tschöp, Marya Shanabrough, Gary Cline, Gerald I. Shulman, Anna Coppola, Xiao Bing Gao, Tamas L. Horvath, Sabrina Diano

Research output: Contribution to journal › Article › peer-review

601 Scopus citations

Abstract

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.

Original language	English
Pages (from-to)	846-851
Number of pages	6
Journal	Nature
Volume	454
Issue number	7206
DOIs	https://doi.org/10.1038/nature07181
State	Published - 14 Aug 2008
Externally published	Yes

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@article{12939e7c1ee04209a4338d47abedf99f,

title = "UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals",

abstract = "The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.",

author = "Andrews, {Zane B.} and Liu, {Zhong Wu} and Nicholas Walllingford and Erion, {Derek M.} and Erzsebet Borok and Friedman, {Jeffery M.} and Tsch{\"o}p, {Matthias H.} and Marya Shanabrough and Gary Cline and Shulman, {Gerald I.} and Anna Coppola and Gao, {Xiao Bing} and Horvath, {Tamas L.} and Sabrina Diano",

note = "Funding Information: Acknowledgements This work was supported by NIH grants to T.L.H., S.D., X.-B.G. and G.I.S., by a New Zealand Foundation for Research Science and Technology (FRST) fellowship to Z.B.A., by grants from the JDRF and American Diabetes Association to S.D., and by a grant from the Michael J. Fox Foundation to T.L.H. We thank B. Lowell for providing breeding pairs of Ucp22/2 mice and M. Sleeman for providing breeding pairs of Ghsr2/2 mice. S.D. thanks A. Lombardi for the discussion on mitochondrial membrane potential measurements. The authors thank V. Pieribone for the use of a spectrofluorophotometer.",

year = "2008",

month = aug,

day = "14",

doi = "10.1038/nature07181",

language = "English",

volume = "454",

pages = "846--851",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7206",

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TY - JOUR

T1 - UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals

AU - Andrews, Zane B.

AU - Liu, Zhong Wu

AU - Walllingford, Nicholas

AU - Erion, Derek M.

AU - Borok, Erzsebet

AU - Friedman, Jeffery M.

AU - Tschöp, Matthias H.

AU - Shanabrough, Marya

AU - Cline, Gary

AU - Shulman, Gerald I.

AU - Coppola, Anna

AU - Gao, Xiao Bing

AU - Horvath, Tamas L.

AU - Diano, Sabrina

N1 - Funding Information: Acknowledgements This work was supported by NIH grants to T.L.H., S.D., X.-B.G. and G.I.S., by a New Zealand Foundation for Research Science and Technology (FRST) fellowship to Z.B.A., by grants from the JDRF and American Diabetes Association to S.D., and by a grant from the Michael J. Fox Foundation to T.L.H. We thank B. Lowell for providing breeding pairs of Ucp22/2 mice and M. Sleeman for providing breeding pairs of Ghsr2/2 mice. S.D. thanks A. Lombardi for the discussion on mitochondrial membrane potential measurements. The authors thank V. Pieribone for the use of a spectrofluorophotometer.

PY - 2008/8/14

Y1 - 2008/8/14

N2 - The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.

AB - The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.

UR - http://www.scopus.com/inward/record.url?scp=49649122302&partnerID=8YFLogxK

U2 - 10.1038/nature07181

DO - 10.1038/nature07181

M3 - Article

C2 - 18668043

AN - SCOPUS:49649122302

SN - 0028-0836

VL - 454

SP - 846

EP - 851

JO - Nature

JF - Nature

IS - 7206

ER -

UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals

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