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

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

Author information

1
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI.
2
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin Province, China.
3
Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI.
4
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
5
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI Department of Chemistry, Brown University, Providence, RI.
6
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI Pathobiology Program, Brown University, Providence, RI hxu@lifespan.org.

Abstract

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.

PMID:
24722245
PMCID:
PMC4141371
DOI:
10.2337/db14-0066
[Indexed for MEDLINE]
Free PMC Article

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