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.

Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion

“…Although lack of MMP12 improved adipogenesis by only 30%, the involvement of this enzyme in adipose tissue regulation is consistent with observations of Mmp12 Ϫ/Ϫ mice, which are prone to obesity (26). This phenotype suggests that MMP12 helps suppress adipose tissue expansion and that adipose tissue DCs could be a major source of that enzyme.…”

“…A list of antibodies used is provided in supplemental Table 2. Cells were sorted on a FACSCanto II cell analyzer, and the leukocyte population was identified on side scatter versus forward scatter plots followed by a propidium iodide (PI Ϫ ) and CD45 ϩ selection (26). A dump gate for CD80, CD86, CD103, CD4, CD8, and DEC205 under FITC was used to verify that Cd45 ϩ Cd11b ϩ Cd11c ϩ MHCII ϩ do not express any of these proteins included.…”

Identification of Matrix Metalloproteinase-12 as a Candidate Molecule for Prevention and Treatment of Cardiometabolic Disease

“…Additionally, OWAT and SWAT from lean and obese human subjects were (Table 2), mirroring the published data regarding its regulation and expression in adipose tissue. (22,37,38) To validate the results from the unbiased in silico approach, the gene and protein expression profiles of Mmp12 in different depots of adipose tissue were analyzed by RT-PCR and western blot, respectively. As reported in previous studies (39) and in agreement with the microarray and meta-analysis results, Mmp12 was significantly upregulated in diet-induced obesity in mice (Figures 2A and B).…”

Matrix metalloproteinases in head and neck cancer: current perspectives

“…MMP12 degrades elastin, type IV collagen, type I gelatin, myelin basic protein, and α 1 -antitrypsin. 13 MMP12 is mainly expressed by macrophages, and is associated with varied pathologic conditions, including inflammation. 13 The domain structure, substrate activities, and biologic functions of the membrane-type MMPs (MT-MMPs) were recently described in an elaborate and elegant review by Itoh. 14 Briefly, MT-MMPs have either a transmembrane domain or a glycosylphosphatidylinositol anchor.…”