Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase

Jung Ting Lee, Nathalie Pamir, Ning Chun Liu, Elizabeth A. Kirk, Michelle M. Averill, Lev Becker, Ilona Larson, Derek K. Hagman, Karen E. Foster-Schubert, Brian Van Yserloo, Karin E. Bornfeldt, Renee C. LeBoeuf, Mario Kratz, Jay W. Heinecke

Research output: Contribution to journalArticle

22 Citations (Scopus)

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,weinvestigated the role ofMMP12in adipose tissue expansion and insulin resistance. In humans,MMP12expression 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. Copyright

Original languageEnglish (US)
Pages (from-to)3409-3420
Number of pages12
JournalEndocrinology
Volume155
Issue number9
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

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Matrix Metalloproteinase 12
Tissue Expansion
Nitric Oxide Synthase Type II
Insulin Resistance
Adipose Tissue
Macrophages
Metalloproteases
Fats
Obese Mice
High Fat Diet
Pathologic Processes
Conditioned Culture Medium
Proteomics
Dendritic Cells
Nitric Oxide
Insulin
Inflammation
Messenger RNA
mouse matrix metallopeptidase 12

ASJC Scopus subject areas

  • Endocrinology

Cite this

Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase. / Lee, Jung Ting; Pamir, Nathalie; Liu, Ning Chun; Kirk, Elizabeth A.; Averill, Michelle M.; Becker, Lev; Larson, Ilona; Hagman, Derek K.; Foster-Schubert, Karen E.; Van Yserloo, Brian; Bornfeldt, Karin E.; LeBoeuf, Renee C.; Kratz, Mario; Heinecke, Jay W.

In: Endocrinology, Vol. 155, No. 9, 01.09.2014, p. 3409-3420.

Research output: Contribution to journalArticle

Lee, JT, Pamir, N, Liu, NC, Kirk, EA, Averill, MM, Becker, L, Larson, I, Hagman, DK, Foster-Schubert, KE, Van Yserloo, B, Bornfeldt, KE, LeBoeuf, RC, Kratz, M & Heinecke, JW 2014, 'Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase', Endocrinology, vol. 155, no. 9, pp. 3409-3420. https://doi.org/10.1210/en.2014-1037
Lee, Jung Ting ; Pamir, Nathalie ; Liu, Ning Chun ; Kirk, Elizabeth A. ; Averill, Michelle M. ; Becker, Lev ; Larson, Ilona ; Hagman, Derek K. ; Foster-Schubert, Karen E. ; Van Yserloo, Brian ; Bornfeldt, Karin E. ; LeBoeuf, Renee C. ; Kratz, Mario ; Heinecke, Jay W. / Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase. In: Endocrinology. 2014 ; Vol. 155, No. 9. pp. 3409-3420.
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AU - Averill, Michelle M.

AU - Becker, Lev

AU - Larson, Ilona

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AU - Bornfeldt, Karin E.

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