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ORIGINAL RESEARCH ARTICLE

Matrix Metalloproteinase-3 Enhances the Free Fatty Acids-Induced VEGF Expression in Adipocytes Through Toll-Like Receptor 2

Toru Kawamura^*, Kentaro Murakami^*, Hideaki Bujo^,1, Hiroyuki Unoki, Meizi Jiang, Toshinori Nakayama and Yasushi Saito^*

^* Department of Clinical Cell Biology, Department of Genome Research and Clinical Application, Department of Applied Translation Research, and Department of Immunology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan

To whom requests for reprints should be addressed at ¹ Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: hbujo{at}faculty.chiba-u.jp

Infiltrated macrophages (M) are believed to cause pathological changes in the surrounding adipocytes through the secretion of active molecules in visceral fat. Matrix metalloproteinase (MMP)-3 is secreted from M, and enhances expression of the inflammatory cytokines through the activation of toll-like receptor (TLR) 2. Visceral adipocytes express high levels of vascular endothelial growth factor (VEGF), and the degree of visceral fat accumulation is associated with the plasma VEGF concentration in obese subjects. The aim of the study is to clarify the role of MMP-3 in the enhancement of the free fatty acids (FFAs)-induced VEGF expression through TLR2 in visceral adipocytes. One mM FFAs induced VEGF mRNA and protein expression in 3T3-L1 adipocytes. The FFAs-induced VEGF expression was mostly mediated by TLR2. A high fat intake increased the VEGF mRNA expression in visceral fat and the VEGF concentration in plasma, accompanied with the increase in the plasma FFAs concentration in mice. These increases were largely inhibited in TLR2-deficient mice. The FFAs-induced VEGF expression was increased in the presence of M-conditioned medium (CM) in adipocytes, and the enhancement was inhibited by a MMP-3 inhibitor or a neutralizing antibody against MMP-3. The active form of MMP-3 induced the VEGF mRNA expression, as well as TLR2, in adipocytes. The increase in the VEGF expression by MMP-3 was inhibited by the treatment with siRNA for TLR2. The enhancement of FFAs-induced TLR2 expression by M-CM was inhibited by blocking of the MMP-3. The increase in the VEGF mRNA expression by M-CM or MMP-3 was partially inhibited by a neutralizing antibody against TNF-. These results indicate that MMP-3 in M-CM enhances the FFAs-induced VEGF expression in adipocytes through the increase in the TLR2 expression. The MMP-3 secreted from the infiltrated M may be a regulator of the VEGF expression in visceral adipocytes.

Key Words: matrix metalloproteinase-3 • toll-like receptor 2 • macrophage • vascular endothelial growth factor • adipocyte • visceral fat