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Objective Genetic variants at the fat mass- and obesity-associated (FTO) locus are strongly associated with obesity-related traits by regulating neighboring genes. Nevertheless, it is possible that FTO protein is directly involved in mechanisms regulating body composition and adiposity. Here, the in vivo biological functions of FTO in the risk for obesity were studied by reviewing murine models. Methods The effects of the locus-specific manipulations of the murine Fto gene on metabolic-related phenotypes in genetically modified mouse models were reviewed and summarized into the following three categories: growth and body composition, eating behaviors, and metabolic homeostasis. Results The mouse models showed different phenotypes depending on target tissues and methods for gene manipulation. Mice harboring deletions or point mutations at the Fto locus had high metabolic rates, while FTO-overexpressing mice showed dyslipidemia. Both deletion and overexpression of the Fto gene led to abnormal eating behaviors. Intriguingly, several phenotypes were differently expressed depending on developmental timing of the genetic manipulations. For instance, a germ line deletion decreased total body fat mass, while the deletion in adult mice increased it. Conclusions The results highlight that FTO is critical not only for body composition but also normal development, and its function might differ depending on the stage of development.