epoetin-alfa and Obesity

Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

Topics: Adiposity; Animals; Diet; Dietary Fats; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Feeding Behavior; Glucose; Hematocrit; Humans; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Recombinant Proteins; Weight Gain

Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of (14)C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

Topics: Animals; Darbepoetin alfa; Diabetes Mellitus, Experimental; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Receptors, Erythropoietin; Recombinant Fusion Proteins; Recombinant Proteins; Time Factors