Receptor Mediated Erythropoietin Metabolic Response and Gender Specific Activity

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Although erythropoietin was initially thought to function only as an erythropoietic agent, animal studies demonstrated non-erythropoietic erythropoietin activity such as neovascularization, cardiovascular protection, accelerated recovery in skeletal muscle injury and protection against diet induced obesity. We found that erythropoietin treatment to increase in hematocrit is accompanied by improved glucose tolerance in mice on normal chow diet and during high fat diet feeding, and the improvement is greatest in young male and female mice. In contrast, erythropoietin regulation of fat mass is more evident during high fat diet feeding and in male mice, increasing with age. In female mice, estrogen is protective against diet induced obesity and erythropoietin regulation of fat mass is not readily apparent. However, estrogen production is reduced with age and older females mice at 6 months of age demonstrate erythropoietin regulation of fat mass during high fat diet feeding. High circulating erythropoietin in mice was associated with altered expression of genes related to lipid metabolism in white adipose tissue. Erythropoietin regulated both fat mass accumulation in white adipose tissue and lipid accumulation in skeletal muscle, and mice with erythropoietin receptor restricted to erythroid tissue showed increased fat mass in adipose tissue and increased lipid droplet formation in skeletal muscle fibers. Animal studies provide evidence of erythropoietin immune modulatory activity via erythropoietin receptor expression on immune cells including macrophages. While erythropoietin stimulated erythropoiesis increased macrophages in the spleen associated with erythroblastic blood islands, erythropoietin treatment decreases macrophage in other non-erythroid tissue. In obese male mice, erythropoietin reduced white adipose tissue associated inflammation, decreased macrophage infiltration and inflammatory cytokine production, shifted macrophages from a pro-inflammatory toward an anti-inflammatory subtype, and increased macrophage STAT3 activation. In female mice, targeted deletion of estrogen receptor alpha in adipose tissue reduced the protective effect of estrogen against diet induced obesity and high fat diet induced obesity resulted in increased inflammation of white adipose tissue. As observed in male mice, erythropoietin treatment in these obese female mice reduced white adipose tissue inflammation and inflammatory cytokine production. Elevated erythropoietin in brain also protected mice against hypothalamus inflammation associated with diet induced obesity. Hypothalamus inflammation in male mice on high fat diet was reduced by concomitant erythropoietin treatment by direct brain infusion using an intracerebralventricular pump or by transgenic erythropoietin expression in brain. Elevated brain EPO decreased inflammatory monocytes, activated microglial cells and inflammatory cytokine production in the hypothalamus. Reduced hypothalamus inflammation was also evident in ovariectomized female mice on high fat diet that express elevated transgenic erythropoietin in brain. Erythropoietin anti-inflammatory activity during high fat diet feeding in white adipose tissue and hypothalamus was independent of change in fat mass and was sex dimorphic, evident in male mice but not in female mice that exhibit estrogen protective activity against obesity. We previously showed the importance of nitric oxide synthase in erythropoietin neuroprotective and cardio-protective activity and the role of neuronal nitric oxide synthase in maintaining the nitric oxide reservoir in skeletal muscle. We will extend this work to examine the role of nitric oxide pathways in erythropoietin metabolic response, particularly in glucose and lipid metabolism in skeletal muscle. Our research program on erythropoietin activity mediated by erythropoietin receptor expression in mouse models demonstrated erythropoietin protective activity in brain, the cardiovascular system, skeletal muscle and metabolic regulation of fat mass and inflammation associated with diet induced obesity. These studies add to understanding of erythropoietin treatment including specific non-erythroid response.