Metabolic control by S6 kinases depends on dietary lipids

PLoS One. 2012;7(3):e32631. doi: 10.1371/journal.pone.0032631. Epub 2012 Mar 7.


Targeted deletion of S6 kinase (S6K) 1 in mice leads to higher energy expenditure and improved glucose metabolism. However, the molecular mechanisms controlling these effects remain to be fully elucidated. Here, we analyze the potential role of dietary lipids in regulating the mTORC1/S6K system. Analysis of S6K phosphorylation in vivo and in vitro showed that dietary lipids activate S6K, and this effect is not dependent upon amino acids. Comparison of male mice lacking S6K1 and 2 (S6K-dko) with wt controls showed that S6K-dko mice are protected against obesity and glucose intolerance induced by a high-fat diet. S6K-dko mice fed a high-fat diet had increased energy expenditure, improved glucose tolerance, lower fat mass gain, and changes in markers of lipid metabolism. Importantly, however, these metabolic phenotypes were dependent upon dietary lipids, with no such effects observed in S6K-dko mice fed a fat-free diet. These changes appear to be mediated via modulation of cellular metabolism in skeletal muscle, as shown by the expression of genes involved in energy metabolism. Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Cell Line
  • Cholesterol / blood
  • Diet, High-Fat / adverse effects
  • Dietary Fats / metabolism*
  • Enzyme Activation
  • Fatty Acids / metabolism
  • Fatty Acids, Nonesterified / metabolism
  • Female
  • Gene Deletion
  • Glucose Intolerance / genetics
  • Glucose Intolerance / prevention & control
  • Leptin / blood
  • Lipid Metabolism* / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Obesity / genetics
  • Obesity / metabolism
  • Phenotype
  • Ribosomal Protein S6 Kinases / deficiency
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism*
  • Triglycerides / blood


  • Amino Acids, Branched-Chain
  • Dietary Fats
  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Leptin
  • Triglycerides
  • Cholesterol
  • Ribosomal Protein S6 Kinases