Sex difference in mouse metabolic response to erythropoietin

Abstract

Erythropoietin (EPO) is the cytokine that regulates red blood cell production. Less understood is the nonerythroid action of EPO, including metabolic regulation of fat accumulation and glucose homeostasis. Although EPO treatment increased hematocrit and improved glucose tolerance in male and female mice, we observed a gender difference in EPO effects in weight control. EPO treatment reduced diet-induced weight gain from 9.6 ± 1.5 to 4.2 ± 1.4 g in male mice ( < 0.001), while the weight gain in female mice was similar (4.7 ± 2.0 g with PBS treatment and 3.3 ± 2.1 g with EPO treatment). EPO treatment also reduced weight gain in ovariectomized female mice, while the effect was abrogated with estradiol supplementation, suggesting that the sex-differential response to EPO was associated with estrogen. Furthermore, mice with targeted deletion of EPO receptor in white adipose tissue exhibited sex-differential phenotype in weight control and glucose sensitivity, and EPO receptor gene expression was reduced in wild-type female mice, suggesting that white adipose tissue plays an integral role in mediating the metabolic effects of EPO. Our data provide evidence for a sex-differential response to EPO in weight control in mice and underscore the potential for gender specific EPO action beyond erythropoiesis.-Zhang, Y., Rogers, H. M., Zhang, X., Noguchi, C. T. Sex difference in mouse metabolic response to erythropoietin.

Effects of experimental manipulation of hematocrit on avian flight performance in high and low altitude conditions

“…Future studies should measure blood and plasma volume to validate this hypothesis. Additionally, it has also been shown that EPO can have a range of non-erythropoietic effects that could potentially enhance exercise performance (Schuler et al, 2012;Zhang et al, 2017), but we did not find any performanceenhancing effect of EPO in our study.…”

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…In ventilatory response in mice, hypoxia induction of EPO modulates ventilatory response, which exhibits a sexdimorphic behavior mediated via interaction with carotid body cells that is also sensitive to ovarian steroids (Soliz et al, 2012). The sex-dependent EPO regulation of fat mass is demonstrated with EPO treatment during high fat diet feeding that reduces fat mass gain in male mice and in female ovariectomized mice but not in female non-ovariectomized mice and not in ovariectomized mice supplemented with estradiol pellets (Zhang et al, 2017). Endogenous EPO signaling may cooperate with estrogen regulation of fat mass in female mice but mask reduction of fat mass by exogenous EPO treatment.…”

“…In EpoR E mice the age dependent accumulation of excess body fat is greater in female that develop obesity and insulin resistance by 4 months of age compared with male mice that exhibit a slower rate of body fat accumulation, becoming obese and insulin resistance at 6 months of age (Teng et al, 2011b; Figures 3A,B). In contrast, fat mass is not altered by EPO treatment in female C57BL/6 mice on normal chow or high fat diet, while EPO treatment in male mice on normal chow decreases fat mass and EPO treatment in male mice on high fat diet reduces the accumulation of fat mass (Zhang et al, 2017; Figures 4A,B). Gender-specific response was also observed in gene expression in white adipose tissue where EPO treatment in mice increased expression in select oxidative genes in male mice on normal chow and on high fat diet, but not in female mice.…”

“…These changes in hematocrit are in marked contrast to the expected increase in hematocrit associated with EPO dose. For example, low dose of 150 U/kg of EPO elevated hematocrits to 60% (Foskett et al, 2011) whilst higher doses of 3000 U/kg of EPO increased hematocrits to 70% in C57BL/6 mice (Zhang et al, 2017).…”

“…In humans, as one ascends to high altitude increased EPO production via HIF regulation induces an EPO response that increases iron utilization for hemoglobin synthesis with expansion of red blood cell production with elevated blood hemoglobin and hematocrit (Gassmann and Muckenthaler, 1985;Smith et al, 2008). The relationship between elevated EPO and reduction in fat mass suggested by metabolic studies in male mice (Teng et al, 2011b;Zhang et al, 2017), raises the possibility that increased EPO levels may explain in part the lower obesity rate reported for humans associated with residence at high altitude (Voss et al, 2013(Voss et al, , 2014. In the United States, obesity prevalence is associated inversely with elevation and urbanization after adjusting for diet, ambient temperature, physical activity, smoking and demographic factors, and among overweight service members (proportion male of 93% at low altitude and 94% at high altitude), those stationed at high altitude were associated with lower incidence of obesity (Voss et al, 2013(Voss et al, , 2014.…”