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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