In this study, we provide evidence that a decreased PTEN expression/activity in the liver, as is observed in patients suffering from obesity-associated fatty liver disease [40], and the associated hepatic steatosis/IR, significantly modulate the pattern of hepatokines expression and secretion, resulting in an increased muscle insulin sensitivity and decreased adiposity in mice. The gene discussed is PTEN; the disease is obesity due to melanocortin 4 receptor deficiency.