FTO and Obesity: Mechanisms of Association

The Fat mass and obesity associated (FTO) gene is a newly identified genetic factor for obesity. However, the exact molecular mechanisms responsible for the effect of FTO on obesity remain largely unknown. Recent studies from genome-wide associated studies reveal that genetic variants in the FTO gene are associated not only with human adiposity and metabolic disorders, but also with cancer, a highly obesity-associated disease as well. Data from animal and cellular models further demonstrate that the perturbation of FTO enzymatic activity dysregulates genes related to energy metabolism, causing the malfunction of energy and adipose tissue homeostasis in mice. The most significant advance about FTO research is the recent discovery of FTO as the first N6-methyl-adenosine (m6A) RNA demethylase that catalyzes the m6A demethylation in α-ketoglutarate - and Fe2+-dependent manners. This finding provides the strong evidence that the dynamic and reversible chemical m6A modification on RNA may act as a novel epitranscriptomic marker. Furthermore, the FTO protein was observed to be partially localized onto nuclear speckles enriching mRNA processing factors, implying a potential role of FTO in regulating RNA processing. This review summarizes the recent progress about biological functions of FTO through disease-association studies as well as the data from in vitro and in vivo models, and highlights the biochemical features of FTO that might be linked to obesity.