Abstract
Erythropoietin (EPO) acts on erythroid progenitor cells to promote their survival and differentiation to mature erythrocytes. Along with this canonical role, EPO is also reported to modulate energy metabolism, resulting in improved glucose tolerance and insulin sensitivity. EPO also stimulates the production of the hormone erythroferrone (ERFE) which acts to suppress hepcidin production, thus increasing dietary iron absorption and mobilizing stored iron for use in erythropoiesis. ERFE (initially termed myonectin) was also reported have an effect on systemic lipid metabolism by promoting the clearance of nonesterifed fatty acids (NEFA) from circulation. As increased levels of circulating NEFA blunt insulin sensitivity and impair glucose tolerance, ERFE‐induced clearance of NEFA after EPO administration would have a beneficial effect on glucose metabolism. The aim of this study was to determine if the known metabolic effect of EPO treatment on glucose homeostasis is mediated by ERFE, produced in response to EPO. Mice lacking Erfe did not differ from wild‐type mice in blood lipid parameters, blood glucose, and glucose or insulin tolerance at baseline or after chronic EPO treatment. Additionally, hepcidin suppression and the response of erythrocyte parameters to chronic EPO treatment were unaffected by the absence of Erfe. These findings suggest that the known beneficial effects of EPO on glucose metabolism are not attributable to an accompanying increase in ERFE production, and that Erfe is dispensable for normal glucose homeostasis. Furthermore, our data indicate that ERFE‐independent mechanisms can suppress hepcidin in response to chronically elevated EPO levels.
Highlights
In vertebrates, most of the body’s iron is contained within hemoglobin in erythrocytes, where it binds oxygen for transport to tissues
We focused on nonesterifed fatty acids (NEFA) levels as treatment with ERFE has been reported to modulate serum NEFA concentrations (Seldin et al 2012)
As reducing circulating levels of NEFA improves insulin sensitivity and glucose tolerance (Santomauro et al 1999), we aimed to test the possibility that beneficial effects of EPO treatment on glucose homeostasis (Allegra et al 1996; Mak 1998; Katz et al 2010; Foskett et al 2011; Alnaeeli et al 2014) are mediated by increased ERFE signaling
Summary
Most of the body’s iron is contained within hemoglobin in erythrocytes, where it binds oxygen for transport to tissues. Erythropoiesis is regulated by erythropoietin (EPO), a glycoprotein hormone produced by the kidney in response to hypoxia. EPO increases erythrocyte production by preventing the programmed cell death of erythroid precursors and promoting their maturation (Koury and Bondurant 1988, 1990). Beyond this canonical effect of EPO in regulating erythropoiesis, EPO indirectly supports erythropoiesis by increasing the production of the hormone erythroferrone (ERFE). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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