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

A Corrigendum to this article was published on 04 June 2009

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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Figure 1: Mitochondrial and transcriptional effects of ghrelin are mediated by UCP2.
Figure 2: Effects of ghrelin on neuronal firing, synaptic plasticity and feeding are mediated by UCP2.
Figure 3: Ghrelin activates an intracellular pathway of fatty acid metabolism.
Figure 4: ROS is a critical regulator of cellular and behavioural responses to ghrelin.

References

  1. Cowley, M. A. et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661 (2003)

    Article  CAS  Google Scholar 

  2. Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neurosci. 9, 381–388 (2006)

    Article  CAS  Google Scholar 

  3. Abizaid, A. et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229–3239 (2006)

    Article  CAS  Google Scholar 

  4. Kamegai, J. et al. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 4797–4800 (2000)

    Article  CAS  Google Scholar 

  5. Diano, S. et al. Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144, 5014–5021 (2003)

    Article  CAS  Google Scholar 

  6. Garcia-Martinez, C. et al. Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation. FASEB J. 15, 2033–2035 (2001)

    Article  CAS  Google Scholar 

  7. Rossmeisl, M. et al. Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo . Eur. J. Biochem. 269, 19–28 (2002)

    Article  CAS  Google Scholar 

  8. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999)

    Article  CAS  Google Scholar 

  9. Coppola, A. et al. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. 5, 21–33 (2007)

    Article  CAS  Google Scholar 

  10. Horvath, T. L. et al. Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J. Neurosci. 19, 10417–10427 (1999)

    Article  CAS  Google Scholar 

  11. Willesen, M. G., Kristensen, P. & Romer, J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316 (1999)

    Article  CAS  Google Scholar 

  12. Sun, Y., Asnicar, M., Saha, P. K., Chan, L. & Smith, R. G. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 3, 379–386 (2006)

    Article  CAS  Google Scholar 

  13. Barazzoni, R. et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 288, E228–E235 (2005)

    Article  CAS  Google Scholar 

  14. Tsubone, T. et al. Ghrelin regulates adiposity in white adipose tissue and UCP1 mRNA expression in brown adipose tissue in mice. Regul. Pept. 130, 97–103 (2005)

    Article  CAS  Google Scholar 

  15. Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000)

    Article  ADS  CAS  Google Scholar 

  16. Horvath, B. et al. Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold. Biochem. Pharmacol. 64, 369–374 (2002)

    Article  CAS  Google Scholar 

  17. Scott, I. D. & Nicholls, D. G. Energy transduction in intact synaptosomes. Influence of plasma-membrane depolarization on the respiration and membrane potential of internal mitochondria determined in situ . Biochem. J. 186, 21–33 (1980)

    Article  CAS  Google Scholar 

  18. Zhang, C. Y. et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab. 3, 417–427 (2006)

    Article  CAS  Google Scholar 

  19. Krauss, S., Zhang, C. Y. & Lowell, B. B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc. Natl Acad. Sci. USA 99, 118–122 (2002)

    Article  ADS  CAS  Google Scholar 

  20. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105, 745–755 (2001)

    Article  CAS  Google Scholar 

  21. Abizaid, A., Gao, Q. & Horvath, T. L. Thoughts for food: brain mechanisms and peripheral energy balance. Neuron 51, 691–702 (2006)

    Article  CAS  Google Scholar 

  22. Horvath, T. L. & Gao, X. B. Input organization and plasticity of hypocretin neurons: possible clues to obesity’s association with insomnia. Cell Metab. 1, 279–286 (2005)

    Article  CAS  Google Scholar 

  23. Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004)

    Article  ADS  CAS  Google Scholar 

  24. Luquet, S., Phillips, C. T. & Palmiter, R. D. NPY/AgRP neurons are not essential for feeding responses to glucoprivation. Peptides 28, 214–225 (2007)

    Article  CAS  Google Scholar 

  25. Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004)

    Article  CAS  Google Scholar 

  26. Kohno, D., Sone, H., Minokoshi, Y. & Yada, T. Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochem. Biophys. Res. Commun. 366, 388–392 (2008)

    Article  CAS  Google Scholar 

  27. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Bergeron, R. et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281, E1340–E1346 (2001)

    Article  CAS  Google Scholar 

  29. Reznick, R. M. & Shulman, G. I. The role of AMP-activated protein kinase in mitochondrial biogenesis. J. Physiol. 574, 33–39 (2006)

    Article  CAS  Google Scholar 

  30. Lam, T. K., Schwartz, G. J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nature Neurosci. 8, 579–584 (2005)

    Article  CAS  Google Scholar 

  31. Wolfgang, M. J. et al. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc. Natl Acad. Sci. USA 104, 19285–19290 (2007)

    Article  ADS  CAS  Google Scholar 

  32. Du, X. et al. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J. Clin. Invest. 116, 1071–1080 (2006)

    Article  CAS  Google Scholar 

  33. Yamagishi, S. I. et al. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J. Biol. Chem. 276, 25096–25100 (2001)

    Article  CAS  Google Scholar 

  34. Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002)

    Article  ADS  CAS  Google Scholar 

  35. Brand, M. D. et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic. Biol. Med. 37, 755–767 (2004)

    Article  CAS  Google Scholar 

  36. Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001)

    Article  ADS  CAS  Google Scholar 

  37. Horvath, T. L., Bechmann, I., Naftolin, F., Kalra, S. P. & Leranth, C. Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res. 756, 283–286 (1997)

    Article  CAS  Google Scholar 

  38. Parton, L. E. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007)

    Article  ADS  CAS  Google Scholar 

  39. Gao, Q. et al. Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nature Med. 13, 89–94 (2007)

    Article  CAS  Google Scholar 

Download references

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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Correspondence to Tamas L. Horvath or Sabrina Diano.

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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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