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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 induced changes in muscle gene expression one week after electrotransfer.Significantly differentially expressed genes are depicted according to gene ontology groups. Control and EPO transfected groups were fed either a normal chow or a high-fat diet for one week. Mean Ct threshold is depicted for each group and red corresponds to a high expression value; green indicates a lower expression value (n = 4–5 in each group).
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pone-0005894-g005: EPO induced changes in muscle gene expression one week after electrotransfer.Significantly differentially expressed genes are depicted according to gene ontology groups. Control and EPO transfected groups were fed either a normal chow or a high-fat diet for one week. Mean Ct threshold is depicted for each group and red corresponds to a high expression value; green indicates a lower expression value (n = 4–5 in each group).

Mentions: Among the 99 analysed genes, EPO transfection resulted in up-regulation of 12 genes and down-regulation of 15 genes after one week, independent of dietary group. To evaluate the differences between functional related genes a gene ontology analysis was performed (Fig. 5). Genes involved in thermogenesis, cytoskeleton and inflammation were up-regulated in response to EPO expression, whereas genes involved in glucose metabolism and transport, proteolysis, stress response, and DNA repair were down-regulated. In agreement with the reduced plasma insulin levels in the high-fat fed EPO mice, genes involved in signalling such as insulin, IRS1 and insulin degrading enzyme were down-regulated in this group. In contrast, genes involved in lipid metabolism, gluconeogenesis, cell-to-cell adhesion, and cell proliferation were up-regulated in the high-fat EPO group.


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 induced changes in muscle gene expression one week after electrotransfer.Significantly differentially expressed genes are depicted according to gene ontology groups. Control and EPO transfected groups were fed either a normal chow or a high-fat diet for one week. Mean Ct threshold is depicted for each group and red corresponds to a high expression value; green indicates a lower expression value (n = 4–5 in each group).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005894-g005: EPO induced changes in muscle gene expression one week after electrotransfer.Significantly differentially expressed genes are depicted according to gene ontology groups. Control and EPO transfected groups were fed either a normal chow or a high-fat diet for one week. Mean Ct threshold is depicted for each group and red corresponds to a high expression value; green indicates a lower expression value (n = 4–5 in each group).
Mentions: Among the 99 analysed genes, EPO transfection resulted in up-regulation of 12 genes and down-regulation of 15 genes after one week, independent of dietary group. To evaluate the differences between functional related genes a gene ontology analysis was performed (Fig. 5). Genes involved in thermogenesis, cytoskeleton and inflammation were up-regulated in response to EPO expression, whereas genes involved in glucose metabolism and transport, proteolysis, stress response, and DNA repair were down-regulated. In agreement with the reduced plasma insulin levels in the high-fat fed EPO mice, genes involved in signalling such as insulin, IRS1 and insulin degrading enzyme were down-regulated in this group. In contrast, genes involved in lipid metabolism, gluconeogenesis, cell-to-cell adhesion, and cell proliferation were up-regulated in the high-fat EPO group.

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