A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling

Nat Commun. 2015 Apr 1:6:6693. doi: 10.1038/ncomms7693.


Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Adipose Tissue / metabolism*
  • Alanine / blood
  • Animals
  • Energy Metabolism*
  • Fibroblast Growth Factors / metabolism*
  • Hypertrophy
  • Lipolysis / genetics
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Proteolysis
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction


  • NR3C1 protein, mouse
  • Receptors, Glucocorticoid
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Alanine