From human genetics to biological insight

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In 2007, SNPs in an intron of the gene FTO were reported to be associated with obesity. At the time, essentially nothing was known about the gene. A few months later, a group of biochemists proposed a role for the gene in demethylation of nucleic acids (RNA or DNA). This week, a group of mouse geneticists present an analysis of a knockout of the gene, and show that the knockouts are resistant to weight gain due to increased energy expenditure.

There’s still quite a ways to go before the mechanism by which FTO contributes to weight variation in humans is understood (oddly enough, there’s some evidence that the mechanism is through increased energy intake rather than expenditure), but people keep chipping away…

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  1. Energy intake vs. expenditure doesn’t affect long-term weight in humans. Storage of fats as triglycerides in fat cells is mostly due to the presence of insulin (the only hormone that serves to trap fat in fat cells rather than free it up for use as fuel). 
    In the Frayling et al 2007 paper, they note that what FTO does may be it’s effect on a neighboring obesity-related gene KIAA1005, in which it is in high LD: 
    FTO is closely adjacent to a gene of unknown function KIAA1005 (Fig. 1 and fig. S2), which is transcribed in the opposite direction. This opens up the possibility that genetic variation [in FTO] affects a regulatory element for KIAA1005; however, there is no obvious such variant within the 47-kb associated region. We conclude that the 47-kb intron within the FTO gene is most likely to contain the predisposing variant(s), but there is, at present, no clear genetic mechanism to explain how this alters the function or expression of FTO, KIAA1005, or more distant genes. 
    KIAA1005 is most highly expressed in the Islets of Langerhans — infinitely more so than in the brain or anywhere else (see their fig S3B). This is the body’s production site of insulin (from the Islets’ B-cells). 
    Because energy intake and expenditure cannot account for long-term fat storage, variation in the FTO / KIAA1005 region must do so by screwing with insulin production, which is consistent with KIAA1005′s primary expression being in the Islets of Langerhans.

  2. it’s difficult to say what’s going on. certainly the demonstration that mouse FTO knockouts gain less weight when put on a high-fat diet makes it a strong candidate for being the relevant gene.

  3. Right, I mean what the mechanism is — doesn’t have to do with eating more or less, or mouse-ercizing more or less, but with how insulin regulates storage of fat rather than burning of fat as fuel.