The biological activities of erythropoietin, the cytokine required for red blood cell production, have been found to extend to non-erythroid tissues due to the expression of the erythropoietin receptor. Erythropoietin promotes metabolic activity and increases mitochondrial function in white adipocytes via PPARa and Sirt1. We found that erythropoietin activated AMPK in adipocytes as well as in white adipose tissue from diet induced obese mice. Erythropoietin increased cellular NAD+ via increased AMPK activity, possibly leading to activation of Sirt1. AMPK knock down reduced erythropoietin mediated increase in cellular oxidative function including the increased oxygen consumption rate, fatty acid utilization and induction of key metabolic genes. Under hypoxic condition, adipocytes were found to generate more reactive oxygen species, and erythropoietin reduced production of reactive oxygen species and increased antioxidant gene expression, suggesting that erythropoietin may provide protection for oxidative stress in adipocytes. AMPK knock down also impaired erythropoietin stimulated increased antioxidant gene expression. These findings suggest AMPK activity contributes to erythropoietin signaling regulating adipocyte cellular redox status and metabolic activity.
