Endogenous Erythropoietin (EPO) provides protection against obesity and heart function. Mice with EPO receptor restricted to erythroid tissue (ΔEPORE mice) become obese, glucose intolerant and insulin resistant. In male mice at 4 months of age, after three weeks of high fat diet feeding, ΔEPORE mice showed an increase in fat mass from to 13 grams compared to fat mass in wild type mice that more than doubled from 4 to grams. EPO treatment (i.p. 3000 U/kg, 3 times/week for three weeks) during high fat diet feeding in wild type mice reduced the increase in fat mass to 3 grams and had a minimal effect on fat mass in ΔEPORE mice. The EPO stimulated increase in hematocrit was comparable in wild type and ΔEPORE mice. Using echocardiography to measure cardiac systolic function and cardiac output after high fat diet feeding, without EPO treatment ejection fraction (%) and fractional shortening (%) of left ventricular contractility were decreased in ΔEPORE mice compared with wild type mice, suggesting that endogenous EPO provided a cardioprotective effect mediated by EPO receptor expression in non-erythroid cells. EPO treatment in wild type mice decreased peak velocity and left ventricular outflow tract velocity but there were no significant changes in ΔEPORE mice, indicating that the decreases in these parameters with EPO administration are independent of EPO stimulated erythropoiesis and mediated by EPO receptor in non-erythroid cells. EPO treatment also decreased ejection fraction and fractional shortening in wild type mice and had no further significant effect in ΔEPORE mice. These data provide evidence that while endogenous EPO may be protective for heart function, high dose EPO administration during high fat diet feeding in wild type mice compromises cardiac function. EPO modulation of heart function requires EPO receptor expression beyond erythroid cells and is distinct from EPO stimulated erythropoiesis.


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

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