Mitogen-activated protein kinase phosphatase 3 (MKP-3)-deficient mice are resistant to diet-induced obesity.
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.
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI.
Bin
B
Feng
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.
Ping
P
Jiao
Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI.
Ynes
Y
Helou
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI.
Yujie
Y
Li
Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Brown University, Warren Alpert Medical School, Providence, RI.
Qin
Q
He
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
Matthew S
MS
Walters
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI Department of Chemistry, Brown University, Providence, RI.
Arthur
A
Salomon
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.
Haiyan
H
Xu
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D059305:Diet, High-Fat; D054642:Dual Specificity Phosphatase 6 / Q000172:deficiency*; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
D014280:Triglycerides; D054642:Dual Specificity Phosphatase 6; D006655:Histone Deacetylases