Previous studies have shown that modulation of insulin signaling in OBs, by genetically decreasing or increasing the levels of INSR expression, either worsens or enhances glucose tolerance and insulin resistance in HFD-fed animals, respectively.31 Furthermore, mice with OB-specific deletion of FoxO1 (FoxO1OB−/−), a negative regulator of insulin signaling, are protected from HFD-induced obesity.3 Consistent with these data, suppression of skeletal mTORC1 activity, a downstream mediator and negative regulator of insulin signaling, protects mice from diet-induced obesity. The gene discussed is INSR; the disease is obesity due to melanocortin 4 receptor deficiency.