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      Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse

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          Abstract

          The strongest BMI–associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.

          Author Summary

          The fat mass and obesity (FTO) gene has one of the strongest links with body mass index (BMI) in the human population. One in six people have the “risk” alteration and weigh 3 kg more than those with the unaltered gene, but it is not understood how this gene influences BMI and obesity. We set out to understand how and where in the body FTO affects food intake, energy expenditure, and body composition using a mouse model that can be manipulated to lack FTO at particular times and/or places. Removing FTO everywhere from conception had a dramatic effect on body composition and resulted in stunted growth and some lethality. Removing FTO everywhere but only in adult animals resulted in better viability and normal growth but, surprisingly, reduced lean mass and increased fat mass with a change in the type of metabolic fuel being used. Finally, we removed FTO from the hypothalamus of adult animals, an important brain region involved in energy metabolism. These animals showed a mild reduction in food intake and weight gain. Our experiments show that FTO has an important role in body composition and that other brain areas outside of the hypothalamus are also important in determining its effects.

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          Most cited references30

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          The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

          Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
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            Inactivation of the Fto gene protects from obesity.

            Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
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              An obesity-associated FTO gene variant and increased energy intake in children.

              Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods. 2008 Massachusetts Medical Society
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                January 2013
                January 2013
                3 January 2013
                : 9
                : 1
                : e1003166
                Affiliations
                [1 ]MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
                [2 ]University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
                [3 ]Department of Statistics, University of Oxford, Oxford, United Kingdom
                [4 ]Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
                [5 ]Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
                [6 ]Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom
                University of Cincinnati, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: FM CDC FMA APC RDC GSHY SO. Performed the experiments: FM CDC SW LT RL YCLT DR APC. Analyzed the data: FM CDC RL GN APC FMA RDC. Contributed reagents/materials/analysis tools: FB VJ GSHY. Wrote the paper: FM CDC FMA APC RDC.

                ¶ These authors also contributed equally to this work.

                Article
                PGENETICS-D-12-01996
                10.1371/journal.pgen.1003166
                3536712
                23300482
                3f21f848-20a8-466a-8607-8599fd18707f
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 August 2012
                : 26 October 2012
                Page count
                Pages: 14
                Funding
                Research was funded by the Medical Research Council and Wellcome Trust (093136). FM and CDC were in receipt of MRC doctoral training studentships. This work was also funded by a MRC Programme Grant G9824984, and phenotyping equipment was supported by MRC Centre for Obesity and Related Metabolic Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Genetic Mutation
                Genetics of Disease
                Genome-Wide Association Studies
                Model Organisms
                Animal Models
                Mouse
                Medicine
                Metabolic Disorders

                Genetics
                Genetics

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