Model of FTO regulation of leptin action and glucose homeostasis through the LepRb-STAT3 signaling pathway. A) The binding of leptin to its receptor triggers the activation of JAK2 and the phosphorylation of STAT3 on a tyrosine residue (Y705). This modification causes the STAT3 protein to relocate to the nucleus, where as a dimer, it regulates gene expression (upregulation of both SOCS3 and LepR and reduction of G6P). Our data further suggest that FTO could be a STAT3-upregulated gene in hepatocytes. B) FTO overexpression reduces Y705 STAT3 phosphorylation, reducing its nuclear translocation and leading to a downregulation of both SOCS3 and LepRb and an upregulation of G6P mRNA levels. Just to opposite, FTO overexpression induces S727 phosphorylation of STAT3, favorizing its mitochondrial localization, where it induces mitochondrial density and function. All these effects are associated in vivo with hyperleptinemia, hyperglycemia, hyperleptinemia and glucose intolerance. Altogether, these data indicate that FTO controls leptin action and glucose metabolism in liver.