Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy

• Published in: The Journal of biological chemistry 2007-08, Vol.282 (35), p.25445-25452
• Main Authors: Ito, Ayaka, Suganami, Takayoshi, Miyamoto, Yoshihiro, Yoshimasa, Yasunao, Takeya, Motohiro, Kamei, Yasutomi, Ogawa, Yoshihiro
• Format: Article
• Language: English
• Subjects: Adipocytes - enzymology; Adipocytes - pathology; Adipose Tissue - enzymology; Adipose Tissue - pathology; Animals; Cell Cycle Proteins - biosynthesis; Cell Movement; Chemokine CCL2 - biosynthesis; Down-Regulation; Dual Specificity Phosphatase 1; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Enzymologic; Hypertrophy; Immediate-Early Proteins - biosynthesis; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Obesity - enzymology; Obesity - pathology; Phosphoprotein Phosphatases - biosynthesis; Phosphorylation; Protein Phosphatase 1; Protein Tyrosine Phosphatases - biosynthesis; RNA, Messenger - biosynthesis; Time Factors; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701549200

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.