title: Metabolomic analysis of akt1-mediated muscle hypertrophy in models of diet-induced obesity and age-related fat accumulation.
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.
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge CB2 1GA, United Kingdom.
authors.forename: Kian-Kai
authors.initials: KK
authors.lastname: Cheng
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akasaki
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lecommandeur
authors.forename: Ross T
authors.initials: RT
authors.lastname: Lindsay
authors.forename: Steven
authors.initials: S
authors.lastname: Murfitt
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D000367:Age Factors; D000818:Animals; D002853:Chromatography, Liquid; D004789:Enzyme Activation / Q000502:physiology*; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D015999:Multivariate Analysis; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Protein kinase B; metabonomics; obesity; type 2 diabetes