Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy.
Monocyte chemoattractant protein-1 (MCP-1), an important chemokine whose expression is increased during the course of obesity, plays a role in macrophage infiltration into obese adipose tissue. This study was designed to elucidate the role of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in the induction of MCP-1 during the course of adipocyte hypertrophy. We examined the time course of MKP-1 and MCP-1 mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation in the adipose tissue from mice rendered mildly obese by a short term high fat diet. We also studied the role of MKP-1 in the induction of MCP-1 in 3T3-L1 adipocytes during the course of adipocyte hypertrophy. MCP-1 mRNA expression was increased, followed by ERK activation and down-regulation of MKP-1, an inducible dual specificity phosphatase to inactivate ERK, in the adipose tissue at the early stage of obesity induced by a short term high fat diet, when macrophages are not infiltrated. Down-regulation of MKP-1 preceded ERK activation and increased production of MCP-1 in 3T3-L1 adipocytes in vitro during the course of adipocyte hypertrophy. Adenovirus-mediated restoration of MKP-1 in hypertrophied 3T3-L1 adipocytes reduced the otherwise increased ERK phosphorylation, thereby leading to the significant reduction of MCP-1 mRNA expression. This study provides evidence that the down-regulation of MKP-1 is critical for increased production of MCP-1 during the course of adipocyte hypertrophy.
Ito
Ayaka
A
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, and Department of Medicine, National Cardiovascular Center Hospital, Osaka, Japan.
Suganami
Takayoshi
T
Miyamoto
Yoshihiro
Y
Yoshimasa
Yasunao
Y
Takeya
Motohiro
M
Kamei
Yasutomi
Y
Ogawa
Yoshihiro
Y
D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology; D000273:Adipose Tissue / Q000201:enzymology / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors; D015854:Up-Regulation
C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases