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Title: The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice

Author
item GAO, XUE - Baylor College Of Medicine
item YONG-HYUN, SHIN - Baylor College Of Medicine
item LI, MIN - Baylor College Of Medicine
item WANG, FEI - Children'S Nutrition Research Center (CNRC)
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)
item ZHANG, PUMIN - Baylor College Of Medicine

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2010
Publication Date: 11/16/2010
Citation: Gao, X., Yong-Hyun, S., Li, M., Wang, F., Tong, Q., Zhang, P. 2010. The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PLoS One. 5(11):e14005.

Interpretive Summary: The genetic changes of the Fto gene were identified to be closely associated with the occurrences of obesity in humans. However, its physiological function remains to be defined. Here we report the generation and analysis of mice carrying a genetic deletion of the Fto gene. We found the mice lacking Fto display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density, but they maintain normal body composition. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of a growth hormone, IGF-1. Moreover, despite the ubiquitous expression of Fto in all tissue, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nervous system to regulate postnatal growth. This study helps us to understand the function of Fto and eliminate the possibility that loss of Fto is responsible for the development of obesity.

Technical Abstract: FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal a-helical domain and an N-terminal double-strand beta-helix domain, which is conserved in Fe (II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth.