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Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.

Original publication




Journal article


Nat Genet

Publication Date





1086 - 1092


Adiposity, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Animals, Area Under Curve, Body Temperature, Circadian Rhythm, Dietary Fats, Energy Metabolism, Feeding Behavior, Female, Glucose, Glucose Tolerance Test, Homeostasis, Male, Mice, Mixed Function Oxygenases, Models, Animal, Motor Activity, Obesity, Oxo-Acid-Lyases