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.
Fischer
Julia
J
Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
Koch
Linda
L
Emmerling
Christian
C
Vierkotten
Jeanette
J
Peters
Thomas
T
Brüning
Jens C
JC
Rüther
Ulrich
U
D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000378:metabolism; D004435:Eating / Q000502:physiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000196:embryology; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D006130:Growth Disorders / Q000235:genetics / Q000503:physiopathology; D006720:Homozygote; D006963:Hyperphagia / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D007652:Oxo-Acid-Lyases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D013564:Sympathetic Nervous System / Q000502:physiology; D013851:Thinness / Q000235:genetics*
D007328:Insulin; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases