Erythropoietin (EPO) is required for erythrocyte production. However, EPO receptor (EpoR) expression extends beyond erythroid tissue. To assess EPO activity on glucose homeostasis and fat mass accumulation, wild type (WT, C57BL/6) mice, ΔEpoRE mice with EpoR restricted to hematopoietic tissue and ΔEpoRWAT mice with targeted EpoR deletion in fat tissue were fed a high fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at age 3, 4, and 6 months. EPO increased hematocrit in all mice and improved glucose tolerance when fat mass was less than 35% which included all female mice. In male WT mice EPO improved glucose tolerance and reduced fat mass which at 6 months was 40% on HFD and below 35% with HFD/EPO treatment. In female mice, estrogen interferes with EPO fat mass regulation. EPO treatment did not affect fat mass in ΔEpoRE mice, indicating that EPO regulation of fat mass is a non-hematopoietic response. EPO improved glucose tolerance in female and only age 3 month male ΔEpoRE mice when fat mass was less than 35%. In male ΔEpoRWAT mice, EPO minimally reduced fat mass indicating that EPO fat mass regulation in males is largely a direct fat tissue response. EPO treatment improved glucose tolerance in male ΔEpoRWAT mice when fat mass was below 35% but not at 6 months when fat mass exceeded 40%. These data demonstrate that EPO improved glucose tolerance when fat mass was below 35%, that the sex-dimorphic EPO regulation of fat mass is primarily mediated by EpoR in fat, and that EPO activity in glucose metabolism and fat mass is differentially regulated and does not follow EPO stimulated erythropoiesis.
H. Rogers: None. C.T. Noguchi: None.
National Institutes of Health