Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. In male mice and ovariectomized female mice on high fat diet (HFD), EPO treatment increased hematocrit, improved glucose tolerance and attenuated body weight gain via reduced fat mass. Estradiol supplementation abrogated the EPO effect on body weight in ovariectomized female mice, providing evidence for estrogen related gender specific EPO action in metabolic regulation. To determine estrogen response in metabolic regulation with EPO treatment, we use the estrogen receptor α knockout (ERαKO) mice and mice with targeted deletion of estrogen receptor alpha in adipose tissue (ERαadipoKO). Male and female ERαKO mice on HFD exhibit increased fat mass and glucose intolerance. EPO treatment on HFD increased hematocrit in both wild type (WT) and ERαKO mice and reduced gain in fat mass in male mice as well as female ERαKO mice but did not affect fat mass in female WT mice. The improvement in glucose tolerance and insulin tolerance with EPO treatment during HFD was significantly greater in female ERaKO mice compared with female WT. We previously demonstrated that specific deletion of EPO receptor in adipose tissue in mice decreases glucose tolerance and insulin sensitivity and increases susceptibility to diet-induced obesity. Although no decrease in body weight was observed in female WT and ERαadipoKO with EPO treatment on HFD, female ERαadipoKO also showed significantly improved glycemic control with EPO treatment compared with WT control. EPO treatment decreased white fat associated gene expression, Psat1 and Wdnm-1like in subcutaneous fat pads from both female ERαKO mice and ERαadipoKO on HFD but not WT female mice. These results confirm the role of estrogen in the sex-differential EPO effect on fat mass regulation and suggest cross talk between EPO and estrogen signaling in metabolic homeostasis and fat mass regulation via estrogen response in white adipose tissue in female mice.


J. Lee: None. H. Rogers: None. C.T. Noguchi: None.

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