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

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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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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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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