The fat mass and obesity-associated (FTO) gene plays a pivotal role in 
regulating body weight and fat mass; however, the underlying mechanisms are 
poorly understood. Here we show that primary adipocytes and mouse embryonic 
fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit 
increased potential for adipogenic differentiation, while MEFs derived from FTO 
knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these 
findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous 
adipocytes. FTO influences adipogenesis by regulating events early in 
adipogenesis, during the process of mitotic clonal expansion. The effect of FTO 
on adipogenesis appears to be mediated via enhanced expression of the 
pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, 
and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide 
novel mechanistic insight into how upregulation of FTO leads to obesity.