In 2007 genome wide sequencing led to the identification of common genetic variations within intronic regions of the human FTO gene that are associated with obesity related traits. To date, neither the consequence of these variations for FTO expression, nor the exact molecular function of the FTO protein are known.
This study shows that inactivation of the murine Fto gene alters the function of the midbrain dopaminergic circuitry. Loss of FTO impairs the dopamine neuron autoreceptor feedback inhibition that depends on dopamine receptors type 2 (DRD2), type 3 (DRD3) and G protein coupled inwardly rectifying potassium channels (GIRKs). This attenuation of the autoinhibitory feedback loop was observed for both whole body Fto-deficient and dopamine neuron restricted Fto knock out (Fto∆DAT) mice. While Fto-deficient mice exhibited deficits in their responses to stimulation with cocaine, Fto∆DAT mice displayed a hypersensitivity to the locomo- tor and reward stimulating effects of cocaine and resembled DRD2 autoreceptor deficient mice.
On the molecular level, FTO encodes a nucleic acid demethylase that is able to remove N6-methyladenosine (m6A) from messenger RNA. Analysis of m6A in mRNA of Fto-deficient midbrain and striatum showed that FTO acts as a m6A demethylase in vivo. Increased methylation, however, was only demonstrated for a subset of all m6A methylated transcripts. This subset included many transcripts important for cell-cell and neuronal signaling. Furthermore, many of these hypermethylated transcripts are components of dopaminergic signaling and some of these displayed a deregulation on the protein level in Fto-deficient mice, such as DRD3, GIRK2 and NMDAR1.
Taken together, FTO, via acting as a m6A demethylase, plays an important role in regulating the dopamine autoinhibitory feedback loop and hence impinges on dopamine circuit function. Malfunction of dopamine signaling has been implicated in a variety of diseases such as depression, schizophrenia or ADHD and therefore poses the question whether FTO genomic variation is associated with diseases other than obesity and whether association with obesity related traits is partly due to alterations in dopamine circuit function
