Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine

Am J Physiol Endocrinol Metab. 2014 Mar 1;306(5):E469-82. doi: 10.1152/ajpendo.00330.2013. Epub 2013 Dec 17.


UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2α/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, β-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.

Keywords: browning; energy metabolism; fibroblast growth factor 21; myokine; uncoupling protein 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Body Composition / physiology
  • Bone Density / physiology
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cell Line
  • Energy Metabolism / drug effects
  • Fibroblast Growth Factors / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Phosphorylation
  • Uncoupling Agents / pharmacology
  • Uncoupling Protein 1


  • Ion Channels
  • Mitochondrial Proteins
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Agents
  • Uncoupling Protein 1
  • fibroblast growth factor 21
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Fibroblast Growth Factors