Abstract
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.
Highlights
Evidence has accumulated suggesting that obesity is a state of chronic, low grade inflammation; it may represent a potential mechanism whereby obesity leads to the metabolic derangements [1,2,3]
Using an in vitro co-culture system composed of adipocytes and macrophages, we have provided evidence that a paracrine loop involving saturated free fatty acids (FFAs) and tumor necrosis factor-␣ (TNF␣) derived from adipocytes and macrophages, respectively, establishes a vicious cycle that aggravates the inflammatory changes; i.e. marked up-regulation of pro-inflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1)3 and TNF␣ and down-regulation of anti-inflammatory adiponectin [6, 7]
We show that MCP-1 mRNA expression is increased, which is followed by extracellular signal-regulated kinase (ERK) activation and mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) down-regulation in the adipose tissue from mice rendered mildly obese by a short term high fat diet, when macrophages are not infiltrated
Summary
Evidence has accumulated suggesting that obesity is a state of chronic, low grade inflammation; it may represent a potential mechanism whereby obesity leads to the metabolic derangements [1,2,3]. We show that MCP-1 mRNA expression is increased, which is followed by ERK activation and MKP-1 down-regulation in the adipose tissue from mice rendered mildly obese by a short term high fat diet, when macrophages are not infiltrated.
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