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FTO, weight, and the mouse

Gene Expression
By Razib Khan
Aug 17, 2009 2:30 AMNov 5, 2019 9:40 AM


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A very thorough paper in PLoS Genetics on the "obesity gene," FTO, A Mouse Model for the Metabolic Effects of the Human Fat Mass and Obesity Associated FTO Gene:

Geneticists have identified many gene regions that cause human disease by using multiple genetic markers in large populations to find gene regions associated with disease. However, it is often not clear precisely which gene in any given region causes the disease or how the gene exerts its functional effect. For example, a gene variant in the non-coding region of FTO enhances obesity risk, but it is not clear if this is an effect of the FTO gene itself or another gene located nearby. We therefore tested whether FTO regulates body weight in the mouse. We found that a single change (mutation) in the sequence coding for the mouse FTO protein decreases the functional activity of FTO and causes reduced fat mass and body weight. Food intake and activity were normal, but the mutant mice had a higher metabolic rate. In addition, their fat mass was lower than that of normal mice when both were fed a high-fat diet. Our study provides direct evidence that FTO directly affects fat mass and thus is likely to have a role in human obesity. As reduced FTO function decreases body weight in mice, it is worth exploring if pharmaceutical agents that inhibit FTO activity might help reduce human obesity.

Here's the effect of FTO in human populations:

In particular, carriers of one copy of the allele weighed on average 1.2 kg more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 kg more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is also associated with increased risk of Type 2 Diabetes. Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO...The authors found that this variation, or a variation in strong LD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity.

Rembmer, FTO is tracking variation within the population, rather than resulting in people who are going to be obese no matter the environment input. Here's the effect of genetic variation in mice (over time):

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