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Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK, Gehl J - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Centre of Inflammation and Metabolism at the Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Pernille.Hoejman.Moeller@rh.regionh.dk

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.

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Related in: MedlinePlus

EPO over-expression increases exogenous palmitate oxidation.One week after EPO electrotransfer C-14 palmitate oxidation was measured in muscle homogenates from transfected muscle, the contralateral tibialis cranialis muscle of the same mouse and control muscle from non-transfected animals. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05, while ¤ indicates significance at p<0.01.
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pone-0005894-g006: EPO over-expression increases exogenous palmitate oxidation.One week after EPO electrotransfer C-14 palmitate oxidation was measured in muscle homogenates from transfected muscle, the contralateral tibialis cranialis muscle of the same mouse and control muscle from non-transfected animals. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05, while ¤ indicates significance at p<0.01.

Mentions: After one week, fat oxidation increased by 64% in the EPO transfected muscles compared to control muscle for both dietary groups (normal: p<0.05, high-fat: p<0.001, n = 8, Fig. 6). Similarly, fat oxidation was increased by 63% and 58% in the contralateral muscle of the EPO transfected mice for the normal and high-fat fed groups, respectively (p<0.05 for both groups, Fig. 6). The oxidative capacity did not differ between the EPO transfected and contralateral muscles, showing that EPO expression in one muscle increases fat oxidation in the whole musculature.


Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK, Gehl J - PLoS ONE (2009)

EPO over-expression increases exogenous palmitate oxidation.One week after EPO electrotransfer C-14 palmitate oxidation was measured in muscle homogenates from transfected muscle, the contralateral tibialis cranialis muscle of the same mouse and control muscle from non-transfected animals. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05, while ¤ indicates significance at p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690401&req=5

pone-0005894-g006: EPO over-expression increases exogenous palmitate oxidation.One week after EPO electrotransfer C-14 palmitate oxidation was measured in muscle homogenates from transfected muscle, the contralateral tibialis cranialis muscle of the same mouse and control muscle from non-transfected animals. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05, while ¤ indicates significance at p<0.01.
Mentions: After one week, fat oxidation increased by 64% in the EPO transfected muscles compared to control muscle for both dietary groups (normal: p<0.05, high-fat: p<0.001, n = 8, Fig. 6). Similarly, fat oxidation was increased by 63% and 58% in the contralateral muscle of the EPO transfected mice for the normal and high-fat fed groups, respectively (p<0.05 for both groups, Fig. 6). The oxidative capacity did not differ between the EPO transfected and contralateral muscles, showing that EPO expression in one muscle increases fat oxidation in the whole musculature.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Centre of Inflammation and Metabolism at the Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Pernille.Hoejman.Moeller@rh.regionh.dk

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.

Show MeSH
Related in: MedlinePlus