The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice Xue Gao 1 , Yong-Hyun Shin2, Min Li2, Fei Wang 3 , Qiang Tong 3 , Pumin Zhang1,2* 1 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America, 2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Pediatrics, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States of America 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 b-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. Citation: Gao X, Shin Y-H, Li M, Wang F, Tong Q, et al. (2010) The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice. PLoS ONE 5(11): e14005. doi:10.1371/journal.pone.0014005 Editor: Krisztian Stadler, Louisiana State University, United States of America Received June 21, 2010; Accepted October 16, 2010; Published November 16, 2010 Copyright: 2010 Gao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The CLAMS experiments were performed using the service of the Mouse Metabolism Core at Baylor College of Medicine which is supported by the BCM Diabetes and Endocrinology Research Center (DERC) grant (P30 DK079638). XG is supported in part by a pilot grant from the DERC. PZ is supported by grants from National Institutes of Health (CA116097, CA122623, and EY019075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: pzhang@bcm.tmc.edu Introduction The mouse gene Fto was first cloned more than a decade ago as one of the several genes deleted in the Fused toes (Ft) mutant mouse created by insertional mutagenesis [1]. However, it did not draw much attention until very recently when its human homolog FTO was implicated in obesity. In 2007, several groups reported that a cluster of SNPs (single nucleotide polymorphism) in the first intron of FTO was highly associated with obesity-related traits and higher obesity risk [2–4]. The association has been further confirmed by other independent studies in different human populations [5–15], thus rendering FTO the most likely culprit for common forms of obesity. Subsequently, several studies suggested those obesity-associated SNPs were correlated with higher energy intake, increased appetite [16–21] without affecting energy expenditure [18–20,22] or physical activity [17,22–24], although one study also reported no association with energy intake [24]. However, since the obesity-associated SNPs do not affect the coding region of FTO, whether the connection to obesity works through the function of FTO per se is still a question, since the SNPs may exert influence on the expression of distant genes other than FTO. The FTO protein contains a double-stranded b-helix fold typical of the members in the Fe(II) and 2-oxoglutarate-dependent oxygenase family [25–27]. This enzyme family has diverse biological functions all based on the similar chemical mechanism [28,29]. Indeed, similar to a number of members in this family, FTO can demethylate single-stranded nucleic acids in vitro [25,26,30]. However, the physiological function and in vivo substrates of FTO are not well defined. Two Fto mutant mouse models have been reported before [31,32]. The complete knockout mice displayed growth retarda- tion and reduced adiposity [31]. The other mice model bearing a missense mutation in Fto developed a lean phenotype later in life while the linear growth remained unaffected [32]. The studies so far seemed to connect the deficiency of FTO with protection of obesity in mice. Here we described the generation and characterization of two mouse models with varying Fto deficiencies. The whole body Fto knockout mice displayed immediate postnatal growth retardation, with shorter body length, lower body weight, and lower bone mineral density than control mice. However, the mutant mice had relatively normal body composition and were still susceptible to diet induced obesity. In another mouse model, Fto was specifically PLoS ONE | www.plosone.org 1 November 2010 | Volume 5 | Issue 11 | e14005