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

Previous studies have shown genome-wide associations between polymorphisms in the gene FTO (fat mass and obesity associated) and type 2 diabetes and obesity, and genetic manipulation of Fto in mice causes feeding dysregulation and body weight changes. Here Hess et al . show that FTO affects the activity and function of midbrain dopaminergic neurons and subsequent reward-related behaviors. The study also shows that FTO acts as a demethylating enzyme for specific mRNAs in vivo , including mRNAs in the dopaminergic signaling pathway. 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.