Fto and Postnatal Growth Figure 5. FtoD/D mice are susceptible to high fat diet-induced obesity. (A, B, C) Lean mass (A), fat mass (B) and total tissue mass (C) of Fto+/+, Fto+/D and FtoD/D mice on high fat diet. (D) Body composition (fat mass/total tissue mass %) of Fto+/+, Fto+/D and FtoD/D mice on high fat diet. P = 0.0055 (male), P = 0.1(female). (E, F) Body length (E) and femur bone mineral density (F) of Fto+/+, Fto+/D and FtoD/D mice on high fat diet. In (A)–(F), all mice were fed on 60 kcal% fat diet for 10 weeks starting from 4-week-old. DEXA measurements were performed at the end of the 10-week period. For each genotype (Fto+/+/Fto+/D/FtoD/D), n = 14/14/12 (male), 11/9/8 (female). Statistical analyses were performed by one-way ANOVA. **P,0.01. All values are mean 6 s.e.m. doi:10.1371/journal.pone.0014005.g005 body knockout, indicating that Fto functions in the brain to regulate growth. The strong growth retardation phenotype in our Fto deletion mice is consistent with that in the previously reported knockout mouse model generated by a slightly different strategy [31]. However, we did not observe a strong lean phenotype in our Fto-deficient mice as reported previously [32,36]. Instead, we detected a trend of increasing fat mass content (fat mass/total tissue mass %) in the mutants when the mice were fed on normal chow, especially in the females. Both male and female knockout mice also responded well to high fat diet and developed obesity. The male mutants were even more susceptible to diet-induced-obesity than the controls. We did recognize that the individual variation in body fat mass was relatively large, even in the control groups, while the lean mass was quite constant among individuals. This variation might have come from both genetic and environmental factors and likely underlie the difference with the previous reports. Still, the absence of the specific lean phenotype and the lack of resistance to diet-induced-obesity in our Fto knockout mice are in contrast with the previous reports. In the initial report of Fto-deficient mice, the mutant mice were stated to have increased enrgy expenditure when compared to controls, which was cited as the reason for the reduction in adiposity in spite of the relative hyperpahgia [31]. This explanantion was recently challenged based on the lack of statistic PLoS ONE | www.plosone.org 7 November 2010 | Volume 5 | Issue 11 | e14005