Mitogen-Activated Protein Kinase Phosphatase 3 (MKP-3)–Deficient Mice Are Resistant to Diet-Induced Obesity
- Bin Feng1,
- Ping Jiao1,2,
- Ynes Helou3,
- Yujie Li1,
- Qin He1,
- Matthew S. Walters4,
- Arthur Salomon5,6 and
- Haiyan Xu1,7⇑
- 1Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI
- 2School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin Province, China
- 3Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI
- 4Department of Genetic Medicine, Weill Cornell Medical College, New York, NY
- 5Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI
- 6Department of Chemistry, Brown University, Providence, RI
- 7Pathobiology Program, Brown University, Providence, RI
- Corresponding author: Haiyan Xu, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0066/-/DC1.
- Received January 15, 2014.
- Accepted April 3, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.