Church and colleagues have generated a ‘knock-in’ mouse model carrying one or two additional copies of Fto, and show that ubiquitous overexpression of FTO leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet.161 That said, although the increase in weight with the overexpression of FTO seems consistent with the ‘lean’ phenotype of FTO deficiency, the increase in food intake seen in these mice is not. At 8 weeks, the mice overexpressing Fto do have reduced fasting leptin levels, which is odd given that obese mice with increased fat mass are normally expected to have increased leptin levels. One could speculate that the hyperphagic phenotype seen in this model is driven by the hypo-leptinaemia.
