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 (Mphi)-secreted MMP on the functional changes in adipocytes using a culture system.


METHODS
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-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 Mphi 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-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.


CONCLUSIONS
Mphi 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.
Unoki
H
H
Division of Applied Translational Research, Chiba University Graduate School of Medicine, Chiba, Japan.
Bujo
H
H
Jiang
M
M
Kawamura
T
T
Murakami
K
K
Saito
Y
Y
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3