FTO Is Expressed in Neurones throughout the Brain and Its Expression Is Unaltered by Fasting

McTaggart, James S.; Lee, Sheena; Iberl, Michaela; Church, Chris; Cox, Roger D.; Ashcroft, Frances M.

doi:10.1371/journal.pone.0027968

Cited by 79 publications

(58 citation statements)

References 34 publications

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“…FTO has been shown to be expressed at high levels in the brain (64)(65)(66), implicating an important role in regulating mRNA methylation. Although details on the relationship between RNA modifications and disease are just beginning to be examined in depth (67), it is worth noting that Gsk-3 is inhibited by the mood-stabilizing drug lithium (9,10).…”

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Faulds

Egelston

Sedivy

et al. 2018

Journal of Biological Chemistry

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Glycogen synthase kinase-3 (Gsk-3) activity regulates multiple signal transduction pathways, and is also a key component of the network responsible for maintaining stem cell pluripotency. Genetic deletion of Gsk-3α and Gsk-3β or inhibition of Gsk-3 activity via small molecules promotes stem cell pluripotency, yet the mechanism underlying the role for Gsk-3 in this process remains ambiguous. Another cellular process that has been shown to affect stem cell pluripotency is mRNA methylation (m 6 A). Here, we describe an intersection between these components -the regulation of m 6 A by Gsk-3. We find that protein levels for the RNA demethylase, FTO (fat mass and obesity-associated protein), are elevated in Gsk-3α;Gsk-3β-deficient mouse embryonic stem cells (ESCs). FTO is normally phosphorylated by Gsk-3, and mass spectrometry identified the sites on FTO that are phosphorylated in a Gsk-3-dependent fashion. Gsk-3 phosphorylation of FTO leads to polyubiquitination, but in Gsk-3 knockout ESCs, that process is impaired, resulting in elevated levels of FTO protein. As a consequence of altered FTO protein levels, mRNAs in Gsk-3 knockout ESCs have 50% less m 6 A than wild-type ESCs, and m 6 A-seq analysis reveals the specific mRNAs that have reduced m 6 A modifications. Taken together, we provide the first evidence for how m 6 A demethylation is regulated in mammalian cells, and sheds light onto a possible novel mechanism by which Gsk-3 activity regulates stem cell pluripotency.Glycogen synthase kinase-3 (Gsk-3) activity is an important regulator of numerous signal transduction pathways (1). Gsk-3 activity is the sum of two largely redundant proteins, Gsk-3α and Gsk-3β, and in general, Gsk-3 is a negative regulator of cellular signaling (2). Rare among kinases, Gsk-3 is active at a basal state, while pathway activation from upstream signaling cascades results in the inhibition of Gsk-3 activity (2). Gsk-3α and Gsk-3β together regulate signal transduction pathways such as Wnt, protein kinase A (PKA), Hedgehog, transforming growth factor-β (TGF-β), nuclear factor of activated T-cells (NF-AT) and phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling in a variety of biological settings (3)(4)(5).Gsk-3 activity can be inhibited through the use of small molecule inhibitors, such as SB- (6)(7)(8), and the clinically relevant mood-stabilizer lithium (9,10); however, a drawback to the use of small molecules to study Gsk-3 function is the potential for off-target effects (11). Cells in which Gsk-3α and Gsk-3β have been genetically deleted allows for a more confident assessment of Gsk-3-specific functions. Therefore, we utilize mouse embryonic stem cells (ESCs) deficient in both Gsk-3α and Gsk-3β (Gsk-3α -/-; Gsk-3β -/-), i.e., Gsk-3 double knockout (DKO), to assess Gsk-3-specific functions (12,13). One prominent phenotype of Gsk-3 DKO ESCs is their persistent pluripotency, assessed by their inability to differentiate into all three germs layers in a teratoma assay, as well as by analysis of global gene expression ...

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Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Faulds

Egelston

Sedivy

et al. 2018

Journal of Biological Chemistry

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“…First, Fto is highly expressed in brain regions controlling feeding and energy expenditure, such as the hypothalamus (1,15). Second, hypothalamic Fto expression is modulated by fasting (1,(16)(17)(18)(19)(20) and restricted access to food (21), although both upregulation (17,18) and downregulation (1,16,19) have been reported, apparently depending on the severity of caloric restriction.…”

Section: Introductionmentioning

confidence: 99%

A link between FTO, ghrelin, and impaired brain food-cue responsivity

Karra

O’Daly

Choudhury³

et al. 2013

J. Clin. Invest.

341

323

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Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N 6 -methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO "obesity-risk" rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N 6 -methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N 6 -methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.Introduction FTO is an AlkB-like 2-oxoglutarate-dependent nucleic acid demethylase of uncertain cellular function (1). Genome-wide association studies (GWAS) have reliably established that SNPs within the first intron of FTO are robustly associated with increased BMI and adiposity across different ages and populations (2-6). Subjects homozygous for the "obesity-risk" A allele of FTO rs9939609 have a 1.7-fold increased risk for obesity compared with subjects homozygous for the low-risk T allele (2). Evidence to date suggests that the association between SNPs in FTO and BMI is predominantly driven by increased energy intake. Subjects homozygous for the obesity-risk A allele of rs9939609 exhibit overall increased ad libitum food-intake (7-9), particularly fat consumption (7, 9-11), and impaired satiety (12, 13). Furthermore, preschool AA children (AA denotes homozygosity for the A obesity-risk allele in the rs9939609 FTO variant) exhibit obesity-prone eating behaviors, including increased food responsiveness and a tendency to eat in

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“…Hypothalamic FTO mRNA levels have been reported to be higher (Fredriksson et al, 2008;Olszewski et al, 2009;Rask-Andersen et al, 2011), decreased (Poritsanos et al, 2011 or without difference (McTaggart et al, 2011) in fasted mice. Fasting was also found to change hepatic FTO mRNA expression, but had no effect on FTO mRNA expression in muscle and adipose tissues both in mice and broiler chickens (Poritsanos et al, 2010;McTaggart et al, 2011;Tiwari et al, 2012). In the present study, all animals had been fasting for 16 h before slaughter, which eliminated the effect of metabolic state and should have no effect on FTO mRNA expression in muscle of pigs in any case.…”

Section: Discussionmentioning

confidence: 99%

Effects of breed, postnatal development, and nutrition on mRNA expression of the FTO gene in porcine muscle and its relationship with intramuscular fat deposition

Tao¹,

Men²,

Deng³

et al. 2013

CZECH J ANIM SCI

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ABSTRACT:The effects of breed, development, and nutrition on mRNA expression of the fat mass and obesityassociated gene (FTO) and its relationship with intramuscular fat (IMF) content in porcine muscle (m. longissimus dorsi; m.l.d.) were estimated. Purebred Jinhua, Zhongbai, Yorkshire, Duroc, Duroc × Zhongbai (DZ), and Duroc × Yorkshire × Landrace (DYL) pigs were used to investigate the effect of breed. Pigs weighing 2.5, 10, 20, 40, 60, and 100 kg were selected to study the effects of different stages of development. To study the effect of nutrition, four diets were selected: corn-soybean (CS), CS with 1.2% conjugated linoleic acid (CLA) or 0.05% creatine monohydrate (CMH), and barley-soybean (BS). All eighty animals were slaughtered, and m.l.d. samples were collected to examine FTO mRNA expression and IMF content. Results showed that breed significantly affected FTO mRNA expression and IMF content. FTO mRNA expression in the studied pigs was in the order: Zhongbai and Yorkshire > Duroc and DZ > Jinhua and DYL. The IMF content ordered by breed was Duroc > DZ > DYL > Jinhua > Zhongbai > Yorkshire. Both FTO mRNA expression and IMF content increased with age of the pigs, with the greatest difference seen between 100 kg pigs and all other weights. In the study, none of the four diets had a significant effect (P > 0.05) on FTO mRNA expression or IMF content. The study demonstrated that FTO mRNA expression increased with increasing body weight and was significantly affected by the breed of pigs. The results showed that FTO mRNA expression had an inconsistent correlation with IMF content between breeds and developmental ages.

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FTO Is Expressed in Neurones throughout the Brain and Its Expression Is Unaltered by Fasting

Cited by 79 publications

References 34 publications

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

A link between FTO, ghrelin, and impaired brain food-cue responsivity

Effects of breed, postnatal development, and nutrition on mRNA expression of the FTO gene in porcine muscle and its relationship with intramuscular fat deposition

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