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

Overview

MeSH

  • Adipocytes
  • Animals
  • Cell Differentiation
  • Diet, High-Fat
  • Female
  • Histone Deacetylases
  • Male
  • Mice
  • Signal Transduction
  • Triglycerides
  • Weight Gain

MeSH Major

  • Dual Specificity Phosphatase 6
  • Liver
  • Obesity

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. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

publication date

  • September 2014

has subject area

  • Adipocytes
  • Animals
  • Cell Differentiation
  • Diet, High-Fat
  • Dual Specificity Phosphatase 6
  • Female
  • Histone Deacetylases
  • Liver
  • Male
  • Mice
  • Obesity
  • Signal Transduction
  • Triglycerides
  • Weight Gain

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4141371

Digital Object Identifier (DOI)

  • 10.2337/db14-0066

PubMed ID

  • 24722245

Additional Document Info

start page

  • 2924

end page

  • 2934

volume

  • 63

number

  • 9