Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance

Diabetes. 2018 Apr;67(4):624-635. doi: 10.2337/db17-0826. Epub 2018 Jan 9.


Stress responses promote obesity and insulin resistance, in part, by activating the stress-responsive mitogen-activated protein kinases (MAPKs), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Stress also induces expression of MAPK phosphatase-1 (MKP-1), which inactivates both JNK and p38 MAPK. However, the equilibrium between JNK/p38 MAPK and MKP-1 signaling in the development of obesity and insulin resistance is unclear. Skeletal muscle is a major tissue involved in energy expenditure and glucose metabolism. In skeletal muscle, MKP-1 is upregulated in high-fat diet-fed mice and in skeletal muscle of obese humans. Mice lacking skeletal muscle expression of MKP-1 (MKP1-MKO) showed increased skeletal muscle p38 MAPK and JNK activities and were resistant to the development of diet-induced obesity. MKP1-MKO mice exhibited increased whole-body energy expenditure that was associated with elevated levels of myofiber-associated mitochondrial oxygen consumption. miR-21, a negative regulator of PTEN expression, was upregulated in skeletal muscle of MKP1-MKO mice, resulting in increased Akt activity consistent with enhanced insulin sensitivity. Our results demonstrate that skeletal muscle MKP-1 represents a critical signaling node through which inactivation of the p38 MAPK/JNK module promotes obesity and insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Dual Specificity Phosphatase 1 / genetics*
  • Dual Specificity Phosphatase 1 / metabolism*
  • Energy Metabolism
  • Humans
  • Insulin Resistance*
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism*
  • Oxygen Consumption
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • MIRN-21 microRNA, mouse
  • MicroRNAs
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse