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

TitleThe fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry.
Publication TypeJournal Article
Year of Publication2013
AuthorsHess ME, Hess S, Meyer KD, Verhagen LAW, Koch L, Brönneke HS, Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF, Franz T, Horvath TL, Rüther U, Jaffrey SR, Kloppenburg P, Brüning JC
JournalNat Neurosci
Date Published2013 Aug
KeywordsAdenine, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Animals, Cocaine, Corpus Striatum, Dopamine, Dopaminergic Neurons, Exploratory Behavior, Female, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Locomotion, Male, Mesencephalon, Methylation, Methyltransferases, Mice, Mice, Inbred C57BL, Mice, Knockout, Mixed Function Oxygenases, Oxo-Acid-Lyases, Phenotype, Quinpirole, Receptors, Dopamine D2, Receptors, Dopamine D3, Reward, RNA Processing, Post-Transcriptional, RNA, Messenger, Signal Transduction

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 N(6)-methyladenosine (m(6)A) 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.

Alternate JournalNat. Neurosci.
PubMed ID23817550
Grant ListR01 NS056306 / NS / NINDS NIH HHS / United States