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 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.

Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues

“…It is worth noting, however, that even within the cohorts of adults tested previously, there is little consistency in reported effects across studies. Moreover, with one exception (14), none of the prior work links FTO genotypic differences to neural differences in canonical reward regions despite the fact that previous studies have demonstrated a causal role of FTO in regulating dopaminergic transmission (12) and also in modulating mesocorticolimbic circuitry in adults (13). The effects reported here in children in ventral striatum function and structure, as well as the voxel-wise whole-brain exploratory analysis, constrain the FTO genotypic differences to canonical reward neurocircuitry.…”

“…Although the FTO gene is highly expressed in the brain (1), the mechanism by which this gene promotes unhealthy eating behaviors remains poorly understood. Previous studies have suggested that FTO alters dopaminergic midbrain circuitry (12,13). Thus, one possibility is that the FTO gene influences the early development and responsivity of reward-related brain structures, thereby predisposing individuals to develop patterns of unhealthy eating.…”

m6a RNA Methylation: The Implications for Health and Disease

“…Hess et al go further to demonstrate increased m 6 A modifications present in mRNAs encoding key components of neuronal signalling, many from the DA pathway itself. This further translated into disrupted expression of these proteins [53]. This indicates that m 6 A methylation plays a critical role in regulating gene transcription and expression of key components in DA signalling, under the direct control of the FTO protein.…”

“…A recent study has outlined a critical role for Fto in the regulation of dopamine (DA) signalling in the midbrain [53]. The link between this demethylase and DA signalling immediately suggests a role for m 6 A methylation as well.…”

“…A modification on the DA signalling system gives it a broad reach, not least in the function and activity of the immune system. For instance the D2-like receptors, which are particularly influenced by m 6 A modifications [53], are found in greater levels on memory and effector CD4 + T lymphocytes than their naive counterparts [64]. Furthermore, this influence extends to the development of T cells, particularly in the thymus [65].…”