Erythropoietin Over-Expression Protects against Diet-Induced Obesity in Mice through Increased Fat Oxidation in Muscles

Abstract

Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01) in EPO transfected obese mice; thus the mice weighed 21.9±0.8 g (control, normal diet,) 21.9±1.4 g (EPO, normal diet), 35.3±3.3 g (control, high-fat diet) and 28.8±2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models

“…This decrease is at least partially associated with reduced amount of fat tissue, especially evident in the leanness of the tg6 mice. Our results are in line with a recent publication demonstrating that targeted overexpression of EPO in muscle tissue of mice protected against diet induced obesity and increased metabolic parameters (Hojman et al 2009). In line with this observation is our finding that EPO is associated with attenuated body weight gain in the ob/ob mice, despite similar food intake as the diluent-treated mice.…”

Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

“…Expression of the EPOR gene has been long thought to be restricted to the erythroid lineage but has since been identified in C2C12 myoblasts (Ogilvie et al 2000, Launay et al 2010, Jia et al 2012) and myotubes (Joshi et al 2011, Jia et al 2012, as well as in rat (Rotter et al 2008) and human skeletal muscle (Lundby et al 2008, Rundqvist et al 2009). Although chronic treatment with EPO in vivo resulted in increased AKT activation (Hojman et al 2009) and enhanced mitochondrial oxidative phosphorylation (Plenge et al 2012) in mouse and human skeletal muscle respectively, it is still unclear whether EPOR is functional and leads to a direct effect of EPO in muscle cells. Our investigation revealed expression of EPOR mRNA in rat L6 myotubes, although to a lesser extent than that in myoblasts, while soleus and EDL muscles displayed virtually no expression.…”

“…Transgenic mice constitutively overexpressing EPO displayed decreased body weight and improved glucose metabolism as compared with WT litter mates (Katz et al 2010). Conversely, long-term exposure to EPO could prevent diet-induced obesity (Hojman et al 2009). While a role of EPO in mediating muscle anabolism has been suggested, evidence that EPO directly targets skeletal muscle is still lacking.…”

Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

“…In mice overexpressing the Epo gene, increased fat oxidation and an up-regulation of genes involved in lipid metabolism in skeletal muscle has been shown [8]. On the other hand, mice with a lack of Epo-R, except for the bone marrow, have a significantly higher body weight, increased fat mass and increased serum TG levels [2,9].…”