Macrophages regulate tumor necrosis factor- expression in adipocytes through the secretion of matrix metalloproteinase-3

• Published in: International Journal of Obesity Vol. 32; no. 6; pp. 902 - 911
• Main Authors: Unoki, H, Bujo, H, Jiang, M, Kawamura, T, Murakami, K, Saito, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-06-2008
• Subjects: Adipocytes; animal models; culture media; cultured cells; dietary fat; enzyme inhibitors; Fatty acids; gene expression; Genes; Genomes; Glucose; Glycerol; human cell lines; in vitro studies; insulin; Insulin resistance; macrophages; Medicine; messenger RNA; Metabolic syndrome; metalloproteinases; mice; protein synthesis; Tissues; tumor necrosis factor-alpha; Tumor necrosis factor-TNF; University graduates; visceral fat; United States > US; Japan
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2008.7

Objective: Adipocytes accumulated in the visceral area change their function to induce tumor necrosis factor-α (TNF-α) secretion with concomitant matrix metalloproteinase (MMP)-3 induction in mice. This study was performed to clarify the role of macrophages (Mphi)-secreted MMP on the functional changes in adipocytes using a culture system. Design: Cultures of 3T3-L1 adipocytes with THP-1 Mphi or the Mphi-conditioned medium were used to investigate the role of Mphi-MMP on the TNF-α gene in 3T3-L1 adipocytes by the addition of MMP inhibitors. For animal experiments, male C57BL/6J mice were rendered insulin resistant by feeding a high-fat diet, and the expression of an M marker F4/80, and MMP-3 genes in mesenteric and subcutaneous fat tissue specimens were examined. Results: Mphi-conditioned media (Mphi-CM) increased the levels of TNF-α mRNA expression in 3T3-L1 adipocytes, and these adipocyte responses were abolished by treatment with GM6001, a broad-spectrum MMP inhibitor, or NNGH (N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid), an MMP-3 inhibitor. The activated form of MMP-3 enhanced glycerol release as well as TNF-α protein secretion from 3T3-L1 adipocytes. The incubation of adipocytes with MMP-3 inhibited insulin-induced glucose uptake in adipocytes. Furthermore, a high-fat intake increased the expression of MMP-3, decreased the insulin-induced glucose uptake of adipocytes and induced expression of F4/80 in mesenteric fat tissue of C57BL/6 mice. Conclusion: M may cause a pathological link with surrounding adipocytes through the secretion of MMP-3 followed by TNF-α expression in adipocytes in visceral fat tissue.