Thomas Gerken

Publications (2)39.9 Total impact

• Source

  Available from: Roger D Cox

  Article: A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene.

  Chris Church, Sheena Lee, Eleanor A L Bagg, James S McTaggart, Robert Deacon, Thomas Gerken, Angela Lee, Lee Moir, Jasmin Mecinović, Mohamed M Quwailid, Christopher J Schofield, Frances M Ashcroft, Roger D Cox
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  ABSTRACT: Human FTO gene variants are associated with body mass index and type 2 diabetes. Because the obesity-associated SNPs are intronic, it is unclear whether changes in FTO expression or splicing are the cause of obesity or if regulatory elements within intron 1 influence upstream or downstream genes. We tested the idea that FTO itself is involved in obesity. We show that a dominant point mutation in the mouse Fto gene results in reduced fat mass, increased energy expenditure, and unchanged physical activity. Exposure to a high-fat diet enhances lean mass and lowers fat mass relative to control mice. Biochemical studies suggest the mutation occurs in a structurally novel domain and modifies FTO function, possibly by altering its dimerisation state. Gene expression profiling revealed increased expression of some fat and carbohydrate metabolism genes and an improved inflammatory profile in white adipose tissue of mutant mice. These data provide direct functional evidence that FTO is a causal gene underlying obesity. Compared to the reported mouse FTO knockout, our model more accurately reflects the effect of human FTO variants; we observe a heterozygous as well as homozygous phenotype, a smaller difference in weight and adiposity, and our mice do not show perinatal lethality or an age-related reduction in size and length. Our model suggests that a search for human coding mutations in FTO may be informative and that inhibition of FTO activity is a possible target for the treatment of morbid obesity.
  PLoS Genetics 09/2009; 5(8):e1000599. · 8.69 Impact Factor
• Source

  Available from: Vladimir Saudek

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

  Thomas Gerken, Christophe A Girard, Yi-Chun Loraine Tung, Celia J Webby, Vladimir Saudek, Kirsty S Hewitson, Giles S H Yeo, Michael A McDonough, Sharon Cunliffe, Luke A McNeill, [......], Marcella Ma, Zorica Jovanovic, I Sadaf Farooqi, Barbara Sedgwick, Inês Barroso, Tomas Lindahl, Chris P Ponting, Frances M Ashcroft, Stephen O'Rahilly, Christopher J Schofield
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  ABSTRACT: 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.
  Science 12/2007; 318(5855):1469-72. · 31.20 Impact Factor