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Metabolomic analysis of akt1-mediated muscle hypertrophy in models of diet-induced obesity and age-related fat accumulation.

Cheng KK, Akasaki Y, Lecommandeur E, Lindsay RT, Murfitt S, Walsh K, Griffin JL - J. Proteome Res. (2014)

Bottom Line: Multivariate statistics highlighted consistent metabolic changes in gastrocnemius muscle following Akt1 activation, which included significant reductions of serine and histidine-containing dipeptides (anserine and carnosine), in addition to increased concentrations of phosphorylated sugars.In old DTG animals, Akt1 activation was found to improve glucose metabolism and confer a beneficial effect in the regression of age-related fat accumulation.This study identifies metabolic changes induced by Akt1-mediated muscle growth and demonstrates a cross-talk between distant organs that leads to a regression of fat mass.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge CB2 1GA, United Kingdom.

ABSTRACT
Akt1 is a serine/threonine kinase that promotes cell growth and survival. Previously, Akt1 activation in a double transgenic (DTG) mouse model fed a high-fat/high-sucrose (HF/HS) diet was found to promote type IIb muscle growth and to lead to a significant reduction in obesity. Here, we have used metabolomics to examine the metabolic perturbations in blood serum and liver and gastrocnemius tissues of the DTG mice. Multivariate statistics highlighted consistent metabolic changes in gastrocnemius muscle following Akt1 activation, which included significant reductions of serine and histidine-containing dipeptides (anserine and carnosine), in addition to increased concentrations of phosphorylated sugars. In addition, Akt1-mediated regression in obesity could be associated with increased glycolysis in gastrocnemius muscle as well as increased gluconeogenesis, glycogenolysis, and ketogenesis in the liver. In old DTG animals, Akt1 activation was found to improve glucose metabolism and confer a beneficial effect in the regression of age-related fat accumulation. This study identifies metabolic changes induced by Akt1-mediated muscle growth and demonstrates a cross-talk between distant organs that leads to a regression of fat mass. The current findings indicate that agents that promote Akt1 induction in muscle have utility in the regression of obesity.

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PLS-DA scores plot of the LC–MS lipidomic data of livertissue show separation between DTG mice fed the chow and HF/HS diets(A). Satisfactory cross-validation plot for the PLS-DA model demonstratinga robust PLS-DA model (B). Group separation was also observed betweencontrols and the DTG mice fed with the HF/HS diet (C). PLS-DA scoresplot of the LC–MS lipidomic data of gastrocnemius tissue showedseparation between DTG mice fed the chow and HF/HS diets (D); themodel passed cross-validation by random permutation test (E).
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fig5: PLS-DA scores plot of the LC–MS lipidomic data of livertissue show separation between DTG mice fed the chow and HF/HS diets(A). Satisfactory cross-validation plot for the PLS-DA model demonstratinga robust PLS-DA model (B). Group separation was also observed betweencontrols and the DTG mice fed with the HF/HS diet (C). PLS-DA scoresplot of the LC–MS lipidomic data of gastrocnemius tissue showedseparation between DTG mice fed the chow and HF/HS diets (D); themodel passed cross-validation by random permutation test (E).

Mentions: For the liver tissue data sets, no model could be built comparingthe control and DTG group on the normal chow diet. However, robustmodels were built comparing both the control animals on chow dietand HF/HS diet (for the PLS-DA model, R2X = 35%; R2Y = 99%; Q2 = 79%, passed cross-validationby random permutation test; data not shown) and the DTG animals onchow diet and HF/HS diet (for the PLS-DA model, R2X = 41%; R2Y = 99%; Q2 = 81%, passedcross-validation by random permutation test; Figure 5A,B). In both cases, this was driven by increases in a rangeof triglycerides in the HF/HS group (for the DTG group: TAG(51:2),PC(43:0), TAG(51:2), PA(30:0), TAG(53:2); PA(30:1), TAG(55:10), TAG(50:2),TAG(54:2), and TAG(53:3)) and a relative reduction of phospholipids(for the DTG group: lyso-PC(17:1)). In addition, a robust model wasformed between the control mice and the DTG mice on a HF/HS diet (forthe PLS-DA model, R2X = 38%; R2Y = 99%; Q2 = 66%, passed cross-validation by random permutationtest; Figure 5C). This model was associatedwith a decrease in triglycerides and diacylglycerides containing longer,polyunsaturated fatty acids (TAG (53:4), TAG(56:3), and TAG(57:7))and an increase in short chain fatty acids (TAG(48:8), TAG(50:2),TAG(46:4), TAG(48:0), TAG(47:6), TAG(48:2), and TAG(44:4)) in theDTG group.


Metabolomic analysis of akt1-mediated muscle hypertrophy in models of diet-induced obesity and age-related fat accumulation.

Cheng KK, Akasaki Y, Lecommandeur E, Lindsay RT, Murfitt S, Walsh K, Griffin JL - J. Proteome Res. (2014)

PLS-DA scores plot of the LC–MS lipidomic data of livertissue show separation between DTG mice fed the chow and HF/HS diets(A). Satisfactory cross-validation plot for the PLS-DA model demonstratinga robust PLS-DA model (B). Group separation was also observed betweencontrols and the DTG mice fed with the HF/HS diet (C). PLS-DA scoresplot of the LC–MS lipidomic data of gastrocnemius tissue showedseparation between DTG mice fed the chow and HF/HS diets (D); themodel passed cross-validation by random permutation test (E).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4286153&req=5

fig5: PLS-DA scores plot of the LC–MS lipidomic data of livertissue show separation between DTG mice fed the chow and HF/HS diets(A). Satisfactory cross-validation plot for the PLS-DA model demonstratinga robust PLS-DA model (B). Group separation was also observed betweencontrols and the DTG mice fed with the HF/HS diet (C). PLS-DA scoresplot of the LC–MS lipidomic data of gastrocnemius tissue showedseparation between DTG mice fed the chow and HF/HS diets (D); themodel passed cross-validation by random permutation test (E).
Mentions: For the liver tissue data sets, no model could be built comparingthe control and DTG group on the normal chow diet. However, robustmodels were built comparing both the control animals on chow dietand HF/HS diet (for the PLS-DA model, R2X = 35%; R2Y = 99%; Q2 = 79%, passed cross-validationby random permutation test; data not shown) and the DTG animals onchow diet and HF/HS diet (for the PLS-DA model, R2X = 41%; R2Y = 99%; Q2 = 81%, passedcross-validation by random permutation test; Figure 5A,B). In both cases, this was driven by increases in a rangeof triglycerides in the HF/HS group (for the DTG group: TAG(51:2),PC(43:0), TAG(51:2), PA(30:0), TAG(53:2); PA(30:1), TAG(55:10), TAG(50:2),TAG(54:2), and TAG(53:3)) and a relative reduction of phospholipids(for the DTG group: lyso-PC(17:1)). In addition, a robust model wasformed between the control mice and the DTG mice on a HF/HS diet (forthe PLS-DA model, R2X = 38%; R2Y = 99%; Q2 = 66%, passed cross-validation by random permutationtest; Figure 5C). This model was associatedwith a decrease in triglycerides and diacylglycerides containing longer,polyunsaturated fatty acids (TAG (53:4), TAG(56:3), and TAG(57:7))and an increase in short chain fatty acids (TAG(48:8), TAG(50:2),TAG(46:4), TAG(48:0), TAG(47:6), TAG(48:2), and TAG(44:4)) in theDTG group.

Bottom Line: Multivariate statistics highlighted consistent metabolic changes in gastrocnemius muscle following Akt1 activation, which included significant reductions of serine and histidine-containing dipeptides (anserine and carnosine), in addition to increased concentrations of phosphorylated sugars.In old DTG animals, Akt1 activation was found to improve glucose metabolism and confer a beneficial effect in the regression of age-related fat accumulation.This study identifies metabolic changes induced by Akt1-mediated muscle growth and demonstrates a cross-talk between distant organs that leads to a regression of fat mass.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge CB2 1GA, United Kingdom.

ABSTRACT
Akt1 is a serine/threonine kinase that promotes cell growth and survival. Previously, Akt1 activation in a double transgenic (DTG) mouse model fed a high-fat/high-sucrose (HF/HS) diet was found to promote type IIb muscle growth and to lead to a significant reduction in obesity. Here, we have used metabolomics to examine the metabolic perturbations in blood serum and liver and gastrocnemius tissues of the DTG mice. Multivariate statistics highlighted consistent metabolic changes in gastrocnemius muscle following Akt1 activation, which included significant reductions of serine and histidine-containing dipeptides (anserine and carnosine), in addition to increased concentrations of phosphorylated sugars. In addition, Akt1-mediated regression in obesity could be associated with increased glycolysis in gastrocnemius muscle as well as increased gluconeogenesis, glycogenolysis, and ketogenesis in the liver. In old DTG animals, Akt1 activation was found to improve glucose metabolism and confer a beneficial effect in the regression of age-related fat accumulation. This study identifies metabolic changes induced by Akt1-mediated muscle growth and demonstrates a cross-talk between distant organs that leads to a regression of fat mass. The current findings indicate that agents that promote Akt1 induction in muscle have utility in the regression of obesity.

Show MeSH
Related in: MedlinePlus