1997-P: Cross Talk between EPO and Estrogen Signaling in Regulation of Fat Mass

Abstract

Erythropoietin (EPO), the cytokine that regulates erythropoiesis, contributes to metabolic regulation in rodents. The increase in red blood cell production with EPO treatment in mice was accompanied by improved glycemic control, and by attenuated body weight gain via reducing fat mass in male mice. No change in body weight was observed in mice with EPO receptor restricted to erythroid tissue, suggesting that EPO regulation of body weight is a non-erythroid response. EPO stimulated decrease in fat mass was observed in ovariectomized female mice on high fat diet, but not after estradiol supplementation or in ovariectomized female mice on normal chow, providing evidence for estrogen related gender specific EPO action in metabolic regulation beyond erythropoiesis. Here we determine the contribution of estrogen response in EPO metabolic regulation by assessing EPO treatment in estrogen receptor α knockout (ERαKO) mice. Male and female ERαKO mice exhibit decreased glucose tolerance, increased fat mass and, in female ERαKO mice, increased lean mass compared with WT control mice. Overall, EPO stimulated increase in hematocrit in male and female ERαKO mice on high fat diet was accompanied by improvement in glucose tolerance comparable to that observed in WT control mice treated with EPO. EPO treatment in male ERαKO and WT mice show significantly reduced the increase in fat mass while on high fat diet compared with saline treatment. Similarly, EPO treatment in female ERαKO mice on high fat diet show reduced fat mass gain compared to saline treatment. In contrast, EPO treatment did not affect fat mass in female WT mice on high fat diet. We also observed that on normal chow diet, EPO treatment was able to reduce fat mass in female ERαKO mice, but not in female WT mice, confirming the role of estrogen in mediating the sex-differential effect of EPO in regulating fat mass. These results are evidence of cross talk between EPO and estrogen for metabolic homeostasis and regulation of body mass in female mice. Disclosure J. Lee: None. H. Rogers: None. C.T. Noguchi: None.