MAP 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, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
- 2School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin Province, China
- 3Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI 02903
- 4Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065
- 5Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903
- 6Department of Chemistry, Brown University, Providence, RI 02903
- 7Pathobiology Program, Brown University, Providence, RI 02903
- *Corresponding Author: Haiyan Xu, E-mail:
MAP kinase phosphatase 3 (MKP-3) is a negative regulator of ERK signaling. Our laboratory has recently demonstrated that MKP-3 plays an important role in obesity-related hyperglycemia by promoting hepatic glucose output. In this study, we show that MKP-3 deficiency attenuates high fat diet (HFD)-induced body weight gain and protects mice from developing obesity-related hepatosteatosis. Triglyceride (TG) contents are dramatically decreased in the liver of MKP-3-/- mice fed on a HFD compared to wild type controls. Absence of MKP-3 also reduces adiposity, possibly through repressing adipocyte differentiation. In addition, MKP-3-/- mice display increased energy expenditure, enhanced peripheral glucose disposal, and improved systemic insulin sensitivity. Global phosphoproteomic studies were performed to search for downstream mediators of MKP-3 action in liver lipid metabolism. Our results reveal that MKP-3 deficiency increases phosphorylation of histone deacetylase 1 (HDAC1) 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 on a HFD. Reduction of HDAC1/2 activities is sufficient to restore TG content of MKP-3-/- primary hepatocytes to the level similar to wild type (WT) cells.
- Received January 15, 2014.
- Accepted April 3, 2014.
- © 2014 by the American Diabetes Association.
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