title: Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase.
abstract: Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14(+)CD206(+) macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b(+)F4/80(+)CD11c(-) macrophages accumulated to a greater extent in MMP12-deficient (Mmp12(-/-)) mice than in wild-type mice (Mmp12(+/+)). Despite being markedly more obese, fat-fed Mmp12(-/-) mice were more insulin sensitive than fat-fed Mmp12(+/+) mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12(-/-) macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion.
authors.affiliation: Departments of Medicine (J.-T.L., N.P., N.-C.L., M.M.A., L.B., K.E.F.-S., B.V.Y., K.E.B., R.C.L., M.K., J.W.H.), Pathology (K.E.B.), and Epidemiology (E.A.K., M.K.), University of Washington, Seattle, Washington 98105; and Fred Hutchinson Cancer Research Center (D.K.H., M.K.), Public Health Sciences, Seattle, Washington 98103.
authors.forename: Jung-Ting
authors.initials: JT
authors.lastname: Lee
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pamir
authors.forename: Ning-Chun
authors.initials: NC
authors.lastname: Liu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kirk
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Averill
authors.forename: Lev
authors.initials: L
authors.lastname: Becker
authors.forename: Ilona
authors.initials: I
authors.lastname: Larson
authors.forename: Derek K
authors.initials: DK
authors.lastname: Hagman
authors.forename: Karen E
authors.initials: KE
authors.lastname: Foster-Schubert
authors.forename: Brian
authors.initials: B
authors.lastname: van Yserloo
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
authors.forename: Renee C
authors.initials: RC
authors.lastname: LeBoeuf
authors.forename: Mario
authors.initials: M
authors.lastname: Kratz
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D007328:Insulin; D052247:Nitric Oxide Synthase Type II; D053508:Matrix Metalloproteinase 12