2007-P: Age-Dependent Metabolic Response to Erythropoietin in Mice

Erythropoietin (EPO), the cytokine required for erythrocyte production, regulates glucose homeostasis and fat mass accumulation in animal models. For example, young (5-6 weeks) mice on high fat diet (HFD) treated with EPO for 5 weeks show a dose dependent increase in hematocrit and reduction in fat mass accumulation/weight gain. To assess potential age and sex dependent EPO metabolic response, C57/Bl6 mice beginning at 3 months, 4 months or 6 months of age were fed normal chow (NC) or high fat diet (HFD) and treated with EPO or saline for up to 6 weeks. After 3 weeks of EPO treatment, all mice exhibited the expected increase in hematocrit (hct up to 70%) that was accompanied by an improvement in glucose tolerance. Body weight gain was unchanged in the 3-month groups, while the 4- and 6-month males on HFD showed a reduced gain in body weight with 3-weeks of EPO treatment. Since earlier studies suggested an increased reduction in fat mass with extended EPO treatment, EPO treatment was continued for three more weeks. At 6 weeks EPO treatment, body weight gain was not affected in the 3-month groups on NC or HFD but was reduced in the 4- and 6-month groups on HFD in male and female mice. These differences in weight gain appear to be due to differences in fat accumulation. However, after 6 weeks EPO treatment, about 66% of the 3-month group, 70% of the 4-month group showed reduced hematocrit below baseline to low as 22% in the 3-month group and 11% in the 4-month group. Mice with the lowest hct showed the greatest impairment in glucose tolerance. In the 6-month group on HFD, EPO treatment for 6 weeks decreased body weight in both males and females. However, hct decreased in all 6-month mice treated with EPO for 6 weeks, falling as low as 15% and the improved glucose tolerance with EPO treatment seen at 3 weeks was no longer apparent. These data suggest an age dependent immune response at 6 weeks of human EPO treatment in mice and production of anti-human EPO antibodies with the potential to also reduce erythropoiesis and glucose tolerance associated with endogenous EPO.