The Role of Erythropoietin in Metabolic Regulation

Abstract

Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response.

Keywords: EPO; EPOR; metabolism; red cells.

Figure 1

EPO affects fat metabolism in multiple tissues other than hematopoietic tissues. The primary function of EPO is to stimulate the proliferation, survival, and differentiation of bone marrow erythroid progenitor cells and regulate the production of erythrocytes. Animal models provide evidence that non-erythroid EPO activity contributes to metabolism and energy homeostasis. EPO regulates lipid metabolism to increase lipolytic gene expression and suppress lipogenic gene expression to promote a lean phenotype in non-erythroid tissues. These non-erythroid tissues include white adipose tissue (WAT), where EPO decreases fat mass accumulation and susceptibility to diet-induced obesity, brown adipose tissue (BAT), where EPO increases oxygen consumption and contributes to the improvement of glucose tolerance and fat mass, skeletal muscle, where EPO improves muscle maintenance and wound healing, and liver, where EPO decreases fat accumulation associated with non-alcoholic fatty liver disease. Created in BioRender. Yin, W. (2025) https://BioRender.com/r49w251.

Figure 2

EPO-EPOR-RUNX1 axis affects fat accumulation. The EPO-EPOR signaling pathway stabilizes RUNX1 in subcutaneous white adipose tissue (scWAT) by inhibiting the ubiquitination of RUNX1 which is required for proteosome degradation. RUNX1 partners with CBFβ to form a heterodimer that regulates transcription via RUNX1 binding to DNA. RUNX1 binding motifs in promoters of lipid metabolism genes contribute to a lean phenotype. The RUNX1 binding motifs act as enhancers in lipolytic genes to increase expression and as suppressers in lipogenic genes to decrease expression. Created in BioRender. Yin, W. (2025) https://BioRender.com/h58j247.