It is possible that EPO directly activates the PI3K/Akt pathway, which overcomes the HFD-induced impairment in the insulin-related signaling, and inhibits the PEPCK and G6Pase expression, attenuating the HFD-induced gluconeogenesis in the liver and contributing to the improvement of glucose intolerance in HFD-fed mice. Here, INS is linked to Glucose intolerance.