Receptor Mediated Erythropoietin Metabolic Response

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Investigation of cytokine regulation of metabolism in animal models is used to gain insight on potential human metabolic response to endogenous erythropoietin and erythropoietin treatment. Genetically modified mouse models demonstrated erythropoietin stimulation of erythropoiesis as well as tissue specific activity of erythropoietin mediated via stimulation of non-erythroid tissue expression of erythropoietin receptor including metabolic and stress response. Erythropoietin administration increased hematocrit and stimulated response in other tissues such as cardiovascular, brain, muscle, and fat. Erythropoietin affected tissue maintenance or repair and metabolic stress response both indirectly and directly mediated via non-erythroid tissue specific erythropoietin receptor expression. In vascular endothelium, erythropoietin stimulated nitric oxide production in endothelial cells and the requirement for neuronal nitric oxide synthase for normal erythropoietin stimulation of erythropoietic response in mice suggests cross talk between erythropoietin and nitric oxide signaling pathways. Mice with erythropoietin receptor restricted to erythroid tissue showed decrease left ventricular outflow tract peak velocity, ejection fraction and fractional shortening, indicating that endogenous non-erythroid erythropoietin response is protective for heart function. While endogenous erythropoietin activity provideed a protective effect on heart function, neuronal nitric oxide synthase contributeed to the negative impact on heart function of high-dose erythropoietin treatment for anemia. Erythropoietin and its receptor are required for red blood cell production. Mice with erythropoietin receptor restricted to erythroid tissue survived through adulthood with no gross morphologic defect. However, these mice became obese, glucose intolerant and insulin resistant with age indicating that erythropoietin contributes to regulation of energy metabolism mediated by erythropoietin receptor expression in non-erythroid tissue. Genetic deletion of erythropoietin receptor in adipose tissue demonstrated a key role for erythropoietin activity in white adipose tissue in mediating its metabolic activity. These mice that lack endogenous erythropoietin activity in adipose tissue exhibited increased fat mass and susceptibility to diet-induced obesity with increase adipocyte size, inflammation in white adipose tissue and increased macrophage infiltration characterized by crown-like structures. Increased erythropoietin levels in male mice increased red blood cell production and hematocrit, improved glucose tolerance and insulin sensitivity and inflammation in white adipose tissue while reducing white adipose tissue expression of lipogenic-associated genes and increasing expression of lipolytic-associated genes. Changes in expression of genes associated with lipid metabolism were linked to erythropoietin stimulated increase in transcription factor RUNX1 protein in white adipose tissue that directly inhibited expression of lipogenic genes and increased expression of lipolytic genes. RUNX1 binding motifs that affect gene transcription were identified in lipid metabolism genes. These RUNX1 binding motifs act as enhancers on lipolytic genes and as silencers on lipogenic genes. Reporter gene assays showed that erythropoietin treatment combined with RUNX1 expression increased activity of the RUNX1 binding motifs from lipolytic genes and decreased activity of the RUNX1 binding motifs from lipogenic genes. Erythropoietin treatment in mice that lack erythropoietin receptor in adipose tissue did not affect expression of these lipogenic and lipolytic genes in white adipose tissue. In wild type mice, erythropoietin treatment decreased white adipose tissue ubiquitin ligase FBXW7 expression and increased RUNX1 stability, providing evidence that erythropoietin regulates energy metabolism in male mice through the erythropoietin – erythropoietin receptor – RUNX1 axis. Other non-hematopoietic tissues contributed to erythropoietin metabolic regulation in mice such as brain and increased cerebral erythropoietin improved metabolism without increase in hematocrit. Erythropoietin treatment also modified lipid metabolism gene expression in brown fat, skeletal muscle and liver, inhibited lipogenic-associated gene expression and increased lipolytic-associated gene expression, mediated by a direct response via erythropoietin receptor expression or an indirect response resulting from erythropoietin stimulation in white adipose tissue. These animal studies suggest that erythropoietin stimulation in human may regulate fat mass and lipid metabolism in addition to stimulating erythropoietic response.