Gender-Dependent EPO Action in Adipose Tissue

Abstract

Erythropoietin (EPO) is a glycoprotein that stimulates the production of red blood cells. Recent studies have shown the nonerythroid effect of EPO involved in metabolic regulation. EPO treatment attenuated body weight gain in male mice on normal chow, high fat diet induced obese mice and ob/ob mice. EPO regulation of body weight is concomitant with reduction in fat mass. EPO improved glycemic control in both male and female obese mouse models. However, the metabolic response to EPO to reduce weight gain primarily via reduced fat mass appears to be gender specific. Although EPO reduced weight gain in 6 month old female mice on high fat diet, regulation of body weight was not observed in young female mice on high fat diet. In contrast, young ovariectomized female mice on high fat diet showed EPO reduction in weight gain. This sex-specific reduction in weight gain is associated with female hormones as the decreased weight gain with EPO treatment in ovariectomized female mice on high fat diet is abrogated with estrogen supplementation. To determine specific in vivo consequences of potential gender differential response of white adipose tissue with EPO treatment, we examined signal transduction in diet induced obese mice following acute EPO treatment. Analyzing white adipose tissue harvested at 0, 30 min and 60 min following single dose administration of EPO (3000 U/kg), we found that EPO activated Erk signaling in white adipose tissue of male mice. In contrast, there was no evidence of acute Erk response in white adipose tissue of female mice following EPO treatment. Erk is known for its involvement in adipocyte differentiation, adiposity, and high-fat diet induced obesity. These data suggest that estrogen is a key modifier in the metabolic response to EPO, in part via EPO regulation of Erk signaling with gender specificity. Together, these results elucidate a potential mechanism for cross talk between EPO and estrogen, and provide a novel insight about gender specific EPO action to control adipose tissue development. Disclosure J. Lee: None. C.T. Noguchi: None.