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Published on: May 4, 2021
Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of
Jung-Ting Lee1, Nathalie Pamir, Ning-Chun Liu
1Departments 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.
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.
Insights
Macrophage metalloelastase (MMP12) promotes insulin resistance but combats adipose tissue expansion. MMP12 deficiency in mice led to increased obesity but improved insulin sensitivity, suggesting a dual role in metabolic health.
Area of Science:
- Biochemistry
- Immunology
- Metabolic Research
Background:
- Macrophage metalloelastase (MMP12) is primarily expressed by mature tissue macrophages and linked to pathological processes.
- Physiological roles of MMP12 remain largely undescribed, despite increased expression in adipose tissue during obesity.
Purpose of the Study:
- To investigate the role of MMP12 in adipose tissue expansion and insulin resistance.
- To explore the correlation between MMP12 expression and metabolic parameters in humans.
Main Methods:
- Proteomic analysis of macrophage-conditioned media.
- High-fat diet induction in wild-type and MMP12-deficient mice.
- Assessment of adipose tissue mass, macrophage accumulation, and insulin sensitivity.
- In vivo and in vitro analysis of nitric oxide synthase (Nos2) expression.
Main Results:
- Human MMP12 expression positively correlated with insulin resistance and specific macrophage markers in adipose tissue.
- Mice lacking MMP12 (Mmp12(-/-)) exhibited greater adipose tissue expansion and macrophage accumulation but enhanced insulin sensitivity when fed a high-fat diet.
- Impaired inducible nitric oxide synthase (Nos2) expression in Mmp12(-/-) macrophages suggests MMP12 mediates nitric oxide production.
Conclusions:
- MMP12 plays a dual role, promoting insulin resistance while potentially limiting adipose tissue expansion.
- MMP12 may influence nitric oxide production during inflammatory processes in adipose tissue.
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