Macrophage Metalloelastase (MMP12) Regulates Adipose Tissue Expansion, Insulin Sensitivity, and Expression of Inducible Nitric Oxide Synthase
Year: 2014
Type: article
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.
Source: Endocrinology
DOI: 10.1210/en.2014-1037
Institutions: University of Washington, Fred Hutch Cancer Center
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1106773923, G1108040131, Cardiovascular Disease and Diabetes Program Project, G2398048825, G2479677842, Quantitative Assessment of HDL Function, S100A9 and S100A8 in Diabetes and Atherosclerosis, G3862606134, Institute for Translational Health Science (KL2), G4779846423, G5240651316, G5342194980, G6183445112, G6401937517, Cell Signaling: Macrovascular Complications of Diabetes, Cardioprotective Mechanisms of HDL, G7511577891, Anti-inflammatory, cholesterol export, and cardioprotective functions of ABCA1, G9000007448, Nutrition Obesity Research Center, Diabetes Research Center, Institutional Career Development Core
OpenAlex ID: W2153456721