Receptor Mediated Erythropoietin Metabolic Response and Gender Specific Activity

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Estrogens are known to play a role in energy metabolism, control of food intake, insulin sensitivity, and lipid metabolism Men and postmenopausal women accumulate more fat in the intra-abdominal depot than premenopausal women and have increased risk of developing insulin resistance, impaired glucose tolerance and obesity associated metabolic complications. In mice, erythropoietin treatment in mice increased hematocrit and improved glucose tolerance, and only males exhibited decreased fat mass and inflammation associated with diet-induced obesity. In female mice, the estrogen is protective against obesity and inflammation associated with high fat diet feeding which interferes with erythropoietin metabolic activity. With ovariectomy, erythropoietin reduced fat mass accumulation during high fat diet feeding but not in ovariectomized mice with estradiol supplementation or in female mice without ovariectomy. We found that estrogen interference in erythropoietin regulation of fat mass was mediated through the estrogen receptor alpha. Mice with deletion of estrogen receptor alpha and intact estrogen receptor beta exhibited increased fat mass, glucose intolerance and insulin resistance with high fat diet feeding. Erythropoietin treatment reduced fat mass in male wild type mice and male and female mice with deletion of estrogen receptor alpha, but not female wild type mice. Improvement in glucose and insulin tolerance with erythropoietin administration was greater in female mice with whole body or fat specific deletion of estrogen receptor alpha compared with wild type controls. The increase metabolic activity by erythropoietin was associated with browning of white adipocytes indicated by reduction in white fat-associated gene expression and increase in brown fat-associated uncoupling protein 1 and transcription factor PRDM16. Erythropoietin stimulated increase of insulin receptor and Glut4 expression in white adipose tissue and decreased serum leptin in female mice lacking estrogen receptor alpha on high fat diet but not in wild type mice. Male and female mice on high fat diet show an increase in adipocyte size that was reduced with erythropoietin treatment. Erythropoietin regulation of adipocyte size required expression of estrogen receptor alpha in adipocytes and was independent of change in fat mass. Improvement of obesity associated inflammation in white adipose tissue in male mice treated with erythropoietin was not evident in female mice. However, erythropoietin treatment in obese female mice with estrogen receptor alpha deleted in adipose tissue reduced inflammation in white adipose tissue characterized by decrease in inducible nitric oxide synthase and TNF-alpha. The erythropoietin response in mice with whole body or adipose tissue specific deletion of estrogen receptor alpha suggest that cross-talk between erythropoietin and estrogen-signaling pathways affects metabolic homeostasis. In female mice, direct estrogen receptor alpha response in adipose tissue blunts erythropoietin stimulated improvement in glycemic control, fat mass and inflammation. Future studies will examine cross-talk of erythropoietin, estrogen, insulin and nitric oxide pathways in mediating erythropoietin response including regulation of glucose and lipid metabolism, and inflammation associated with diet-induced obesity.