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The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry

Nature Neuroscience volume 16, pages 1042–1048 (2013)Cite this article

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Abstract

Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron–specific Fto knockout mice show attenuated activation of G protein–coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor–mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N6-methyladenosine (m6A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.

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Figure 1: FTO is expressed in DA neurons and controls responses to cocaine.
Figure 2: Cocaine-induced locomotor activity and dopamine release is attenuated in Fto-deficient mice.
Figure 3: Fto deficiency alters D2R-dependent responses of DA neurons.
Figure 4: DA neuron–restricted Fto deficiency impairs D2-like receptor signaling.
Figure 5: Loss of FTO leads to a reduction in GIRK currents in conventional Fto-deficient and FtoΔDAT mice.
Figure 6: DA neuron–restricted Fto deficiency phenocopies loss of D2 autoreceptors.
Figure 7: FTO demethylates mRNAs involved in DA signaling.

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References

  1. Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  Google Scholar 

  2. Yeo, G.S.H. FTO and obesity: a problem for a billion people. J. Neuroendocrinol. 24, 393–394 (2012).

    Article  Google Scholar 

  3. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    Article  CAS  Google Scholar 

  4. Cecil, J.E., Tavendale, R., Watt, P., Hetherington, M.M. & Palmer, C.N.A. An obesity-associated FTO gene variant and increased energy intake in children. N. Engl. J. Med. 359, 2558–2566 (2008).

    Article  CAS  Google Scholar 

  5. Wardle, J., Llewellyn, C., Sanderson, S. & Plomin, R. The FTO gene and measured food intake in children. Int. J. Obes. (Lond.) 33, 42–45 (2009).

    Article  CAS  Google Scholar 

  6. Ho, A.J. et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc. Natl. Acad. Sci. USA 107, 8404–8409 (2010).

    Article  CAS  Google Scholar 

  7. Sobczyk-Kopciol, A. et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 106, 739–748 (2011).

    Article  Google Scholar 

  8. Choudhry, Z. et al. Association between obesity-related gene FTO and ADHD. Obesity (Silver Spring) doi:10.1002/oby.20444 (20 March 2013).

  9. Fischer, J. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009).

    Article  CAS  Google Scholar 

  10. Boissel, S. et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 85, 106–111 (2009).

    Article  CAS  Google Scholar 

  11. Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate–dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).

    Article  CAS  Google Scholar 

  12. McTaggart, J.S. et al. FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PLoS ONE 6, e27968 (2011).

    Article  CAS  Google Scholar 

  13. Gulati, P. et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl. Acad. Sci. USA 110, 2557–2562 (2013).

    Article  CAS  Google Scholar 

  14. Cheung, M.K., Gulati, P., O'Rahilly, S. & Yeo, G.S.H. FTO expression is regulated by availability of essential amino acids. Int. J. Obes. (Lond.) 37, 744–747 (2013).

    Article  CAS  Google Scholar 

  15. Han, Z. et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464, 1205–1209 (2010).

    Article  CAS  Google Scholar 

  16. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).

    Article  CAS  Google Scholar 

  17. Meyer, K.D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    Article  CAS  Google Scholar 

  18. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    Article  CAS  Google Scholar 

  19. Díaz-Torga, G. et al. Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. Endocrinology 143, 1270–1279 (2002).

    Article  Google Scholar 

  20. García-Tornadu, I. et al. Neurotransmitter modulation of the GHRH-GH axis. Front. Horm. Res. 38, 59–69 (2010).

    Article  Google Scholar 

  21. Sibley, D.R. New insights into dopaminergic receptor function using antisense and genetically altered animals. Annu. Rev. Pharmacol. Toxicol. 39, 313–341 (1999).

    Article  CAS  Google Scholar 

  22. Beaulieu, J.-M. & Gainetdinov, R.R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63, 182–217 (2011).

    Article  CAS  Google Scholar 

  23. Hope, B.T. et al. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).

    Article  CAS  Google Scholar 

  24. Di Chiara, G. & Bassareo, V. Reward system and addiction: what dopamine does and doesn't do. Curr. Opin. Pharmacol. 7, 69–76 (2007).

    Article  CAS  Google Scholar 

  25. Jones, S.R. et al. Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat. Neurosci. 2, 649–655 (1999).

    Article  CAS  Google Scholar 

  26. Bello, E.P. et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat. Neurosci. 14, 1033–1038 (2011).

    Article  CAS  Google Scholar 

  27. Ye, J.H., Zhang, J., Xiao, C. & Kong, J.-Q. Patch-clamp studies in the CNS illustrate a simple new method for obtaining viable neurons in rat brain slices: glycerol replacement of NaCl protects CNS neurons. J. Neurosci. Methods 158, 251–259 (2006).

    Article  CAS  Google Scholar 

  28. Hommel, J.D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).

    Article  CAS  Google Scholar 

  29. Ekstrand, M.I. et al. Progressive parkinsonism in mice with respiratory-chain–deficient dopamine neurons. Proc. Natl. Acad. Sci. USA 104, 1325–1330 (2007).

    Article  CAS  Google Scholar 

  30. Anzalone, A. et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J. Neurosci. 32, 9023–9034 (2012).

    Article  CAS  Google Scholar 

  31. Jia, G. et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 582, 3313–3319 (2008).

    Article  CAS  Google Scholar 

  32. Seeman, P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin. Ther. Targets 10, 515–531 (2006).

    Article  CAS  Google Scholar 

  33. Le Foll, B., Gallo, A., Le Strat, Y., Lu, L. & Gorwood, P. Genetics of dopamine receptors and drug addiction: a comprehensive review. Behav. Pharmacol. 20, 1–17 (2009).

    Article  CAS  Google Scholar 

  34. Johnson, P.M. & Kenny, P.J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat. Neurosci. 13, 635–641 (2010).

    Article  CAS  Google Scholar 

  35. Wang, G.J. et al. Brain dopamine and obesity. Lancet 357, 354–357 (2001).

    Article  CAS  Google Scholar 

  36. Klein, T.A. et al. Genetically determined differences in learning from errors. Science 318, 1642–1645 (2007).

    Article  CAS  Google Scholar 

  37. Klöckener, T. et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat. Neurosci. 14, 911–918 (2011).

    Article  Google Scholar 

  38. Rae, J., Cooper, K., Gates, P. & Watsky, M. Low access resistance perforated patch recordings using amphotericin B. J. Neurosci. Methods 37, 15–26 (1991).

    Article  CAS  Google Scholar 

  39. Kyrozis, A. & Reichling, D.B. Perforated-patch recording with gramicidin avoids artifactual changes in intracellular chloride concentration. J. Neurosci. Methods 57, 27–35 (1995).

    Article  CAS  Google Scholar 

  40. Lacey, M.G., Mercuri, N.B. & North, R.A. On the potassium conductance increase activated by GABAB and dopamine D2 receptors in rat substantia nigra neurones. J. Physiol. (Lond.) 401, 437–453 (1988).

    Article  CAS  Google Scholar 

  41. Takigawa, T. & Alzheimer, C. G protein-activated inwardly rectifying K+ (GIRK) currents in dendrites of rat neocortical pyramidal cells. J. Physiol. (Lond.) 517, 385–390 (1999).

    Article  CAS  Google Scholar 

  42. Cruz, H.G. et al. Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system. Nat. Neurosci. 7, 153–159 (2004).

    Article  CAS  Google Scholar 

  43. Ungless, M.A., Whistler, J.L., Malenka, R.C. & Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001).

    Article  CAS  Google Scholar 

  44. Lacey, M.G., Mercuri, N.B. & North, R.A. Two cell types in rat substantia nigra zona compacta distinguished by membrane properties and the actions of dopamine and opioids. J. Neurosci. 9, 1233–1241 (1989).

    Article  CAS  Google Scholar 

  45. Richards, C.D., Shiroyama, T. & Kitai, S.T. Electrophysiological and immunocytochemical characterization of GABA and dopamine neurons in the substantia nigra of the rat. Neuroscience 80, 545–557 (1997).

    Article  CAS  Google Scholar 

  46. Goodarzi, H., Elemento, O. & Tavazoie, S. Revealing global regulatory perturbations across human cancers. Mol. Cell 36, 900–911 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Alber, B. Hampel, H. Wratil and Y. Masekowitz for excellent technical assistance. We also thank C. Mason for assistance with MeRIP-Seq peak calling. We thank the European Conditional Mouse Mutagenesis Program (EUCOMM) for providing mice with knock in of the β-galactosidase gene into the Fto gene and N.G. Larsson (Max Planck Institute for Biology of Ageing, Cologne, Germany) for providing Dat-Cre mice. This work was supported by US National Institutes of Health grant R01 NS056306 (S.R.J.), the Deutsche Forschungsgemeinschaft (Br1492-7/1 to J.C.B. and KL 762/2-2 to P.K.) and the Kompetenznetz Adipositas (Competence Network for Obesity) funded by the German Federal Ministry of Education and Research (FKZ: 01GI1122A to J.C.B.).

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Author notes

  1. Martin E Hess and Simon Hess: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute for Neurological Research, Cologne, Germany

    Martin E Hess, Linda A W Verhagen, Hella S Brönneke & Jens C Brüning

  2. Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne, Germany

    Martin E Hess, Linda A W Verhagen, Linda Koch, Hella S Brönneke, Sabine D Jordan, Bengt F Belgardt & Jens C Brüning

  3. Center of Molecular Medicine Cologne (CMMC), Cologne, Germany

    Martin E Hess, Simon Hess, Linda A W Verhagen, Linda Koch, Hella S Brönneke, Sabine D Jordan, Bengt F Belgardt, Peter Kloppenburg & Jens C Brüning

  4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

    Martin E Hess, Simon Hess, Linda A W Verhagen, Linda Koch, Hella S Brönneke, Sabine D Jordan, Bengt F Belgardt, Peter Kloppenburg & Jens C Brüning

  5. Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, Cologne, Germany

    Martin E Hess, Linda A W Verhagen, Linda Koch, Hella S Brönneke, Sabine D Jordan, Bengt F Belgardt & Jens C Brüning

  6. Institute for Zoology, University of Cologne, Cologne, Germany

    Simon Hess & Peter Kloppenburg

  7. Department of Pharmacology, Weill Medical College, Cornell University, New York, New York, USA

    Kate D Meyer & Samie R Jaffrey

  8. Mouse Phenotyping Facility, CECAD, Cologne, Germany

    Hella S Brönneke

  9. Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcelo O Dietrich & Tamas L Horvath

  10. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcelo O Dietrich & Tamas L Horvath

  11. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcelo O Dietrich & Tamas L Horvath

  12. Institute for Computational Biomedicine, Weill Medical College, Cornell University, New York, New York, USA

    Yogesh Saletore & Olivier Elemento

  13. Max Planck Institute for the Biology of Ageing, Cologne, Germany

    Thomas Franz

  14. Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Düsseldorf, Germany

    Ulrich Rüther

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Contributions

M.E.H., S.H., K.D.M., L.A.W.V., L.K., H.S.B., M.O.D., S.D.J., Y.S., O.E., B.F.B., T.F. and T.L.H. performed experiments, analyzed data and contributed to writing the paper. U.R. provided reagents and transgenic mice for this study. S.R.J. and P.K. analyzed data and contributed to writing the paper. M.E.H., S.H. and J.C.B. conceived the study and wrote the manuscript. All authors agreed on the final version of the manuscript.

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Correspondence to Jens C Brüning.

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Hess, M., Hess, S., Meyer, K. et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16, 1042–1048 (2013). https://doi.org/10.1038/nn.3449

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