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UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals
Open accessAbstract
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.
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“This notion may explain the importance of UCP2 as a ROS scavenger to keep a physiological ROS level that allows correct NPY and AgRP expression in the hypothalamus ([6](#B6)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [6]
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Metadata
- Authors
- Andrews, Z. B., Liu, Z.-W., Walllingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschöp, M. H., Shanabrough, M., Cline, G., Shulman, G. I., Coppola, A., Gao, X.-B., Horvath, T. L., & Diano, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Hubei University of Medicine (CN)
- University of Cincinnati (US)
- Yale University (US)
- Corresponding author
- Diano, Sabrina
- ORCID
- Venue
- Nature
- Published
- 2008-07-30
- Volume
- 454
- Issue
- 7206
- Pages
- 846-851
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4101536
- OpenAlex
- W1988803699
- Cited by
- 710
- References
- 40
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 21 · 2023: 21 · 2022: 33 · 2021: 31 · 2020: 25 · 2019: 23 · 2018: 40 · 2017: 55 · 2016: 42 · 2015: 39 · 2014: 51 · 2013: 69 · 2012: 66
- FWCI
- 23.63
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-06-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R01AG022880)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040936)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ghrelin, UCP2, NPY/AgRP neurons, arcuate nucleus, hypothalamus, mitochondrial respiration, mitochondrial proliferation, fatty acid oxidation, AMPK, carnitine palmitoyltransferase 1, free radicals, oxidative stress, proopiomelanocortin neurons, synaptic plasticity, dietary intake, appetite regulation, G protein-coupled receptor signaling
- MeSH terms
- Uncoupling Protein 2, Animals, Carnitine O-Palmitoyltransferase, Fatty Acids, Feeding Behavior, Gene Expression Regulation, Hypothalamus, Ion Channels, Mitochondria, Neurons, Neuropeptide Y, Phosphorylation, Synapses, Reactive Oxygen Species, Mitochondrial Proteins, Mice, Membrane Potential, Mitochondrial, Agouti-Related Protein, Ghrelin
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