Limits...
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.

Show MeSH

Related in: MedlinePlus

EPO expression is associated with muscle hypertrophy.The muscle hypertrophic response was evaluated 5 weeks after DNA electrotransfer in mice placed on the regular chow diet. Each group consisted of 8 mice. For A and B, data from muscles from control mice (control), the contra lateral leg of the EPO transfected mice (contralateral), and the EPO transfected leg (EPO) are shown. Means±SEM are depicted. A) Total muscle weight, B) phosporylated Akt determined by Western Blotting, C) expression of muscle fibre protein (Q-PCR) in control and EPO transfected muscles, and D) muscle stamina in % of the control leg. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2690401&req=5

pone-0005894-g002: EPO expression is associated with muscle hypertrophy.The muscle hypertrophic response was evaluated 5 weeks after DNA electrotransfer in mice placed on the regular chow diet. Each group consisted of 8 mice. For A and B, data from muscles from control mice (control), the contra lateral leg of the EPO transfected mice (contralateral), and the EPO transfected leg (EPO) are shown. Means±SEM are depicted. A) Total muscle weight, B) phosporylated Akt determined by Western Blotting, C) expression of muscle fibre protein (Q-PCR) in control and EPO transfected muscles, and D) muscle stamina in % of the control leg. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05.

Mentions: To examine the phenotypic consequences of EPO expression on the transfected muscle, mice were electrotransferred with EPO in 1 leg and received a chow diet and doxycycline for 5 weeks. As shown in Fig. 2A, EPO expression induced significant increases in muscle mass in the transfected muscles compared to the contra lateral control muscle (P = 0.046, n = 8) and muscles from untreated control mice (P = 0.00015, n = 8). The increase in muscle weight tended to correlate positively with the Hgb level (P = 0.078, n = 10). The contra lateral muscles tended to weigh more than the control muscles (P = 0.086). The total protein concentration per g muscle remained unchanged, indicating that the increased muscle volume was due to hypertrophy and not edema formation (data not shown). Electroporation alone did not have any effect on muscle mass (data not shown).


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 expression is associated with muscle hypertrophy.The muscle hypertrophic response was evaluated 5 weeks after DNA electrotransfer in mice placed on the regular chow diet. Each group consisted of 8 mice. For A and B, data from muscles from control mice (control), the contra lateral leg of the EPO transfected mice (contralateral), and the EPO transfected leg (EPO) are shown. Means±SEM are depicted. A) Total muscle weight, B) phosporylated Akt determined by Western Blotting, C) expression of muscle fibre protein (Q-PCR) in control and EPO transfected muscles, and D) muscle stamina in % of the control leg. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005894-g002: EPO expression is associated with muscle hypertrophy.The muscle hypertrophic response was evaluated 5 weeks after DNA electrotransfer in mice placed on the regular chow diet. Each group consisted of 8 mice. For A and B, data from muscles from control mice (control), the contra lateral leg of the EPO transfected mice (contralateral), and the EPO transfected leg (EPO) are shown. Means±SEM are depicted. A) Total muscle weight, B) phosporylated Akt determined by Western Blotting, C) expression of muscle fibre protein (Q-PCR) in control and EPO transfected muscles, and D) muscle stamina in % of the control leg. Statistical significance was tested by Student's t-test with Bonferroni corrections for multiple testing. * indicates significance at p<0.05.
Mentions: To examine the phenotypic consequences of EPO expression on the transfected muscle, mice were electrotransferred with EPO in 1 leg and received a chow diet and doxycycline for 5 weeks. As shown in Fig. 2A, EPO expression induced significant increases in muscle mass in the transfected muscles compared to the contra lateral control muscle (P = 0.046, n = 8) and muscles from untreated control mice (P = 0.00015, n = 8). The increase in muscle weight tended to correlate positively with the Hgb level (P = 0.078, n = 10). The contra lateral muscles tended to weigh more than the control muscles (P = 0.086). The total protein concentration per g muscle remained unchanged, indicating that the increased muscle volume was due to hypertrophy and not edema formation (data not shown). Electroporation alone did not have any effect on muscle mass (data not shown).

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