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.
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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 Ucp2-/- mice and M. Sleeman for providing breeding pairs of Ghsr-/- 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.
Author Contributions Z.B.A., S.D. and T.L.H. designed, executed and performed analysis of experiments and wrote the paper. N.W., D.M.E. and A.C. contributed to the execution of the experiments. M.S. and E.B. contributed to the execution of electron microscopy experiments and analysis of the electron microscopic data. Z.-W.L. carried out electrophysiological recordings. X.-B.G. supervised and analysed the electrophysiological experiments. G.C. and G.I.S. designed, performed and analysed the LCFA CoA and NEFA measurements. J.M.F. and M.H.T. provided critical models and reagents for the study and contributed to the data analyses and discussions.
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Andrews, Z., Liu, ZW., Walllingford, N. et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008). https://doi.org/10.1038/nature07181
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DOI: https://doi.org/10.1038/nature07181
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