Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity

Diabetes. 2014 Sep;63(9):2924-34. doi: 10.2337/db14-0066. Epub 2014 Apr 10.


Mitogen-activated protein kinase phosphatase 3 (MKP-3) is a negative regulator of extracellular signal-related kinase signaling. Our laboratory recently demonstrated that MKP-3 plays an important role in obesity-related hyperglycemia by promoting hepatic glucose output. This study shows that MKP-3 deficiency attenuates body weight gain induced by a high-fat diet (HFD) and protects mice from developing obesity-related hepatosteatosis. Triglyceride (TG) contents are dramatically decreased in the liver of MKP-3(-/-) mice fed an HFD compared with wild-type (WT) controls. The absence of MKP-3 also reduces adiposity, possibly by repressing adipocyte differentiation. In addition, MKP-3(-/-) mice display increased energy expenditure, enhanced peripheral glucose disposal, and improved systemic insulin sensitivity. We performed global phosphoproteomic studies to search for downstream mediators of MKP-3 action in liver lipid metabolism. Our results revealed that MKP-3 deficiency increases the phosphorylation of histone deacetylase (HDAC) 1 on serine 393 by 3.3-fold and HDAC2 on serine 394 by 2.33-fold. Activities of HDAC1 and 2 are increased in the livers of MKP-3(-/-) mice fed an HFD. Reduction of HDAC1/2 activities is sufficient to restore TG content of MKP-3(-/-) primary hepatocytes to a level similar to that in WT cells.

Publication types

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

MeSH terms

  • Adipocytes / cytology
  • Animals
  • Cell Differentiation / physiology
  • Diet, High-Fat
  • Dual Specificity Phosphatase 6 / deficiency*
  • Female
  • Histone Deacetylases / metabolism
  • Liver / metabolism*
  • Male
  • Mice
  • Obesity / prevention & control*
  • Signal Transduction / drug effects
  • Triglycerides / metabolism
  • Weight Gain


  • Triglycerides
  • Dual Specificity Phosphatase 6
  • Histone Deacetylases