Erythropoietin Non-hematopoietic Tissue Response and Regulation of Metabolism During Diet Induced Obesity

Abstract

Erythropoietin (EPO) receptor (EPOR) determines EPO response. High level EPOR on erythroid progenitor cells gives rise to EPO regulated production of red blood cells. Animal models provide evidence for EPO activity in non-hematopoietic tissue mediated by EPOR expression. Beyond erythropoiesis, EPO activity includes neuroprotection in brain ischemia and trauma, endothelial nitric oxide production and cardioprotection, skeletal muscle wound healing, and context dependent bone remodeling affecting bone repair or bone loss. This review highlights examples of EPO protective activity in select non-hematopoietic tissue with emphasis on metabolic response mediated by EPOR expression in fat and brain and sex-specific regulation of fat mass and inflammation associated with diet induced obesity. Endogenous EPO maintains glucose and insulin tolerance and protects against fat mass accumulation and inflammation. Accompanying the increase in erythropoiesis with EPO treatment is improved glucose tolerance and insulin response. During high fat diet feeding, EPO also decreases fat mass accumulation in male mice. The increased white adipose tissue inflammation and macrophage infiltration associated with diet induced obesity are also reduced with EPO treatment with a shift toward an anti-inflammatory state and decreased inflammatory cytokine production. In female mice the protective effect of estrogen against obesity supersedes EPO regulation of fat mass and inflammation, and requires estrogen receptor alpha activity. In brain, EPOR expression in the hypothalamus localizes to proopiomelanocortin neurons in the arcuate nucleus that promotes a lean phenotype. EPO stimulation of proopiomelanocortin neurons increases STAT3 signaling and production of proopiomelanocortin. Cerebral EPO contributes to metabolic response, and elevated brain EPO reduces fat mass and hypothalamus inflammation during diet induced obesity in male mice without affecting EPO stimulated erythropoiesis. Ovariectomy abrogates the sex-specific metabolic response of brain EPO. The sex-dimorphic EPO metabolic response associated with fat mass accumulation and inflammation during diet induced obesity provide evidence for crosstalk between estrogen and EPO in their anti-obesity potential in female mice mediated in part via tissue specific response in brain and white adipose tissue. Endogenous and exogenous EPO response in non-hematopoietic tissue demonstrated in animal models suggests additional activity by which EPO treatment may affect human health beyond increased erythropoiesis.

Keywords: erythropoietin; erythropoietin receptor; gender-specific; hypothalamus; inflammation; microglial; obesity.

FIGURE 1

Erythropoietin activity in erythroid and select non-hematopoietic tissues. The primary function of EPO is to regulate the production of red blood cells from erythroid progenitor cells that express high level of EPOR. EPOR expression in non-hematopoietic tissue provides for EPO response that includes brain for neuroprotection and metabolic response, cardiovascular system for cardioprotection and endothelial regulation of vascular tone and oxygen delivery, skeletal muscle maintenance and wound healing, bone remodeling, and metabolic response in white adipose tissue including sex-dimorphic regulation of fat mass and inflammation associated with diet induced obesity.

FIGURE 2

Erythropoietin regulation of fat mass in mice is sex-specific. Male and female ΔEPOR _E mice with EPOR restricted to erythroid tissue exhibit increased gain in body weight and fat mass on normal chow diet and become obese. Male, but not female, wild type (C57BL/6) mice fed high fat diet become obese while male mice on high fat diet and treated with EPO show increase hematocrit without change in fat mass. Ovariectomy eliminates the protective effect of estrogen against diet induced obesity in females and ovariectomized mice fed high fat diet become obese, but not ovariectomized mice treated with EPO.

FIGURE 3

Brain erythropoietin reduction of hypothalamus inflammation during high fat diet induced obesity in mice is sex-specific. Male wild type (WT) (C57BL/6) mice fed high fat diet show increased inflammation in the arcuate region of the hypothalamus with increase microglial activation and recruitment of inflammatory myeloid cells. Male tg21 mice with elevated transgenic EPO production in brain are protected from hypothalamus inflammation associated with high fat diet feeding. Estrogen is protective in female mice against hypothalamus inflammation associated with high fat diet feeding that is only apparent in WT mice after ovariectomy and the protective effects of elevated brain EPO becomes evident in ovariectomized tg21 mice.