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

Objective: Adipocytes accumulated in the visceral area change their function to induce tumor necrosis factor-alpha (TNF-alpha) secretion with concomitant matrix metalloproteinase (MMP)-3 induction in mice. This study was performed to clarify the role of macrophages (M phi)-secreted MMP on the functional changes in adipocytes using a culture system. Design: Cultures of 3T3-L1 adipocytes with THP-1 M phi or the M phi-conditioned medium were used to investigate the role of M phi-MMP on the TNF-alpha 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 phi marker F4/80, and MMP-3 genes in mesenteric and subcutaneous fat tissue specimens were examined. Results: M phi-conditioned media (M phi-CM) increased the levels of TNF-alpha 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-alpha 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 phi may cause a pathological link with surrounding adipocytes through the secretion of MMP-3 followed by TNF-alpha expression in adipocytes in visceral fat tissue.