Dual specificity mitogen-activated protein (MAP) kinase phosphatase-4 plays a potential role in insulin resistance.
Insulin is the key hormone that controls glucose homeostasis. Dysregulation of insulin function causes diabetes mellitus. Among the two major forms of diabetes, type 2 diabetes accounts for over 90% of the affected population. The incidence of type 2 diabetes is highly related to obesity. To find novel proteins potentially involved in obesity-related insulin resistance and type 2 diabetes, a functional expression screen was performed to search for genes that negatively regulate insulin signaling. Specifically, a reporter system comprised of the PEPCK promoter upstream of alkaline phosphatase was used in a hepatocyte cell-based assay to screen an expression cDNA library for genes that reverse insulin-induced repression of PEPCK transcription. The cDNA library used in this study was derived from the white adipose tissue of ob/ob mice, which are highly insulin-resistant. The mitogen-activated dual specificity protein kinase phosphatase 4 (MKP-4) was identified as a candidate gene in this screen. Here we show that MKP-4 is expressed in insulin-responsive tissues and that the expression levels are up-regulated in obese insulin-resistant rodent models. Heterologous expression of MKP-4 in preadipocytes significantly blocked insulin-induced adipogenesis, and overexpression of MKP-4 in adipocytes inhibited insulin-stimulated glucose uptake. Our data suggest that MKP-4 negatively regulates insulin signaling and, consequently, may contribute to the pathogenesis of insulin resistance.
Xu
Haiyan
H
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. haiyan.xu@mpi.com
Dembski
Marlene
M
Yang
Qing
Q
Yang
Daseng
D
Moriarty
Ann
A
Tayber
Olga
O
Chen
Hong
H
Kapeller
Rosana
R
Tartaglia
Louis A
LA
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D054637:Dual-Specificity Phosphatases; D015971:Gene Expression Regulation, Enzymologic; D015723:Gene Library; D017930:Genes, Reporter; D005822:Genetic Vectors; D005947:Glucose / Q000493:pharmacokinetics; D005979:Glutathione Peroxidase; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018076:DNA, Complementary; D007328:Insulin; D011506:Proteins; C014149:phosphoenolpyruvate carboxykinase ferroactivator protein, rat; D012313:RNA; D005979:Glutathione Peroxidase; D000469:Alkaline Phosphatase; D054637:Dual-Specificity Phosphatases; C484491:Dusp9 protein, mouse; D017027:Protein Tyrosine Phosphatases; D005947:Glucose