MAP Kinase Phosphatase 3 (MKP-3) Deficient Mice Are Resistant to Diet Induced-Obesity

  1. Haiyan Xu1,7,*
  1. 1Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
  2. 2School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin Province, China
  3. 3Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI 02903
  4. 4Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065
  5. 5Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903
  6. 6Department of Chemistry, Brown University, Providence, RI 02903
  7. 7Pathobiology Program, Brown University, Providence, RI 02903
  1. *Corresponding Author: Haiyan Xu, E-mail: hxu{at}lifespan.org

Abstract

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.

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