The Metabolic Effect of Chronic Elevated Erythropoietin in Tg6 Mice

Abstract

Erythropoietin (EPO) is the cytokine required for erythrocyte production. However, EPO receptor (EpoR) expression is not restricted to erythroid tissue and non-hematopoietic EPO action has been associated with the regulation of glucose homeostasis and fat mass accumulation in animal models. The hemizygous transgenic tg6 mouse (PDGF- promoter/human EPO cDNA) overexpresses EPO, allowing for the study of chronic elevated levels of EPO. Tg6 mice exhibit a hematocrit of 80-90%, almost twice that of their wild type (wt) littermates. The elevated EPO also alters their glucose metabolism. In both males and females, tg6 mice exhibit significantly lower fasting glucose and improved glucose tolerance with significantly reduced blood glucose levels during a 2-hour glucose tolerance test (GTT). EPO treatment in male wt mice reduces fat mass and body weight compared to saline treatment. Similarly, tg6 mice with chronic elevated EPO have been reported to exhibit reduced body mass compared with control mice. We find that male tg6 mice tend to have reduced body weight, becoming significant with age and due to an associated decrease in fat mass, and a trend toward reduced food intake. In contrast, while female tg6 mice show significant decreases in fat mass, their total body weight is similar to control mice due in part to an increase in lean body mass. These data suggest that metabolically, tg6 mice show improved glucose metabolism compared to control mice associated with a decrease fat store in both male and female mice, and with a sex-specific reduction in body weight in male mice. In addition, the increase in lean body mass in female mice counters the weight loss associated with decrease fat mass resulting in no apparent change in body weight. Disclosure H. Rogers: None. O. Gavrilova: None. C.T. Noguchi: None.