Two recent, large whole-genome association studies (GWAS) in European populations have associated a ϳ47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4°C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the A y , Lep ob , Lepr db , Cpe fat , or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed "ciliopathy." FTM has recently been shown to be a ciliary basal body protein.obesity; hypothalamus; adipose tissue; CUTL1 HERITABILITY OF ADIPOSITY, which reflects genetic contribution to the phenotype within a specific environment, is high, and it is variously estimated at 40 -60% (28, 49). The search for the underlying genes for obesity-using conventional linkage, association, and candidate gene approaches-has generated a large number of positive findings, many of which have not been replicated (e.g., 19, 25, 32, 37, 55, 67). Among the reasons for lack of consistent replication may be the relatively small population sizes, few markers genotyped, and blunt phenotypes. The recent generation of high-density single nucleotide polymorphism (SNP) and haplotype maps (International HapMap project; http://www.hapmap.org/) has revolutionized the field of human quantitative genetics. Applied to large, suitably phenotyped groups of subjects, whole-genome association studies (GWAS) are implicating novel genes not previously considered based on extant understanding of the molecular physiology of specific phenotypes. The discovery of the "Fat Mass and Obesity Associated gene" (FTO) as a potentially important contributor to human adiposity is such an example.In two GWAS involving a total of ϳ42,000 obese and nonobese subjects, dose-dependent highly significant effects of specific SNPs on chr. 16 have been associated with increased body mass index (BMI) (14, 52). In agreement with these results, Dina et al. (8) identified an association between rs1121980 ...
