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Hess ME, Hess S, Meyer KD, Verhagen LA, 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. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci. 2013 Aug ; 16(8):1042-8. Pubmed Abstract

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

Comment by:  Gavin Reynolds
Submitted 28 August 2013
Posted 28 August 2013

FTO and Dopamine Function—A Role in Schizophrenia?
The FTO gene has intrigued molecular genetics since its importance in obesity was recognized in the first major GWAS of body weight and diabetes (Frayling et al., 2007). This finding has been much replicated, although the mechanism underlying association of FTO polymorphisms with obesity has, until recently, been elusive. A recent paper has raised further questions relating to its function. The finding that an FTO knockout in mice can influence dopaminergic activity leads us to speculate whether this gene might be important in schizophrenia and antipsychotic drug action.

FTO codes for fat mass and obesity associated protein, which is, not surprisingly, found in some hypothalamic neurons important in the control of food intake and body weight. In this context it has already been related to the antipsychotic drug action; the established effect of an FTO polymorphism on obesity appears to be even greater in chronically -treated schizophrenia, although it is not associated with initial antipsychotic-induced weight gain (Reynolds et al., 2013). However, FTO is also widely expressed in neurons throughout the brain and elsewhere in the body (McTaggart et al., 2011). Recently, it has been discovered to be associated with a variety of other morbidities not directly related to metabolic dysfunction and independent of any effect on body mass. These include Alzheimer's disease (AD), in which FTO may interact with effects of the established AD risk gene ApoE (Keller et al., 2011), depression (Samaan et al., 2012), and attention deficit hyperactivity disorder (Choudhry et al., 2013).

Its biochemical activity might provide some clues as to why genetic variation in FTO has such a wide variety of effects. FTO protein appears to be a nucleic acid demethylase, of whichwith its major activity is in adenosine demethylation in of RNA (Jia et al., 2011). This means that it may play a role in the regulation of mRNA translation; interestingly, it also has apparent effects on DNA methylation, indicating a potential role in transcriptional regulation (Almén et al., 2012).

Hess and colleagues observed that the phenotypic effects of an FTO knockout in mice were similar to those of a dopamine D2 receptor knockout and asked whether FTO might therefore influence dopaminergic function. They showed FTO was also expressed in dopamine neurons and that its absence, while not affecting the morphology of those cells, impaired some of the neuronal and behavioral effects of cocaine. These effects seem to be associated with a specific influence on methylation of certain mRNAs, notably those associated with components of the dopamine signaling pathway.

This raises some interesting questions relating to schizophrenia and its treatment, perhaps most obviously how FTO might provide a novel antipsychotic drug target. FTO inhibition is an active area of research for future anti-obesity medication; this approach could conceivably identify compounds with effects on dopaminergic activity resulting in an antipsychotic efficacy. Of course, such targeting of dopamine systems does not address the primary pathology of schizophrenia in GABAergic and/or glutamatergic systems. Moreover, much more needs to be understood about the role of FTO as an epigenetic regulator of gene expression. Nevertheless, this study of its importance in dopaminergic function suggests that FTO deserves further investigation in the context of schizophrenia and its treatment, in addition to a possible importance in mechanisms of drug dependence.

References:

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11; 316(5826):889-94. Abstract

Reynolds GP, Yevtushenko OO, Gordon S, Arranz B, San L, Cooper SJ. The obesity risk gene FTO influences body mass in chronic schizophrenia but not initial antipsychotic drug-induced weight gain in first-episode patients. Int J Neuropsychopharmacol. 2013 Jul; 16(6):1421-5. Abstract

McTaggart JS, Lee S, Iberl M, Church C, Cox RD, Ashcroft FM. FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PLoS One. 2011; 6(11):e27968. Abstract

Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L, Graff C. The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis. 2011; 23(3):461-9. Abstract

Samaan Z, Anand S, Zhang X, Desai D, Rivera M, Pare G, Thabane L, Xie C, Gerstein H, Engert JC, Craig I, Cohen-Woods S, Mohan V, Diaz R, Wang X, Liu L, Corre T, Preisig M, Kutalik Z, Bergmann S, Vollenweider P, Waeber G, Yusuf S, Meyre D. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. Mol Psychiatry. 2012 Nov 20. Abstract

Choudhry Z, Sengupta SM, Grizenko N, Thakur GA, Fortier ME, Schmitz N, Joober R. Association between obesity-related gene FTO and ADHD. Obesity (Silver Spring). 2013 Mar 20. Abstract

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011 Dec; 7(12):885-7. Abstract

Almén MS, Jacobsson JA, Moschonis G, Benedict C, Chrousos GP, Fredriksson R, Schiöth HB. Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics. 2012 Mar; 99(3):132-7. Abstract

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