Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Sep 15, 2017; 8(9): 422-428
Published online Sep 15, 2017. doi: 10.4239/wjd.v8.i9.422
Expression of matrix metalloproteinase-11 is increased under conditions of insulin resistance
Biagio Arcidiacono, Eusebio Chiefari, Anna Elisa Laria, Sebastiano Messineo, Francesco Luciano Bilotta, Domenico Britti, Daniela Patrizia Foti, Anna Foryst-Ludwig, Ulrich Kintscher, Antonio Brunetti
Biagio Arcidiacono, Eusebio Chiefari, Anna Elisa Laria, Sebastiano Messineo, Francesco Luciano Bilotta, Domenico Britti, Daniela Patrizia Foti, Antonio Brunetti, Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy
Anna Foryst-Ludwig, Ulrich Kintscher, Institute of Pharmacology, Center for Cardiovascular Research, 10117 Berlin, Germany
Author contributions: Arcidiacono B contributed to research data and wrote the first draft of the manuscript; Foti DP and Britti D contributed to data analysis and interpretation of data; Chiefari E, Laria AE, Messineo S and Bilotta FL contributed to research data; Foryst-Ludwig A contributed to animal studies; Kintscher U contributed reagents and data analysis; Brunetti A contributed to discussion and wrote the final version of the manuscript.
Institutional review board statement: All procedures performed in the study involving animal models were reviewed and approved by the local ethic committee.
Institutional animal care and use committee statement: All animal procedures were performed according to the guidelines of the Charité universitätsmedizin Berlin and were approved by the Landsamt für Gesundheit und Soziales (Berlin, Germany) for the use of laboratory animals and according to the current version of the German Law on protection of animals for scientific purposes.
Conflict-of-interest statement: The authors declare no conflict of interest related to this study and publication.
Data sharing statement: There is no additional data available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Antonio Brunetti, MD, PhD, Professor of Endocrinology, Department of Health Sciences, University “Magna Græcia” of Catanzaro, Viale Europa (Località Germaneto), 88100 Catanzaro, Italy. brunetti@unicz.it
Telephone: +39-0961-3694368 Fax: +39-0961-996087
Received: January 30, 2017
Peer-review started: February 12, 2017
First decision: March 28, 2017
Revised: April 11, 2017
Accepted: May 3, 2017
Article in press: May 5, 2017
Published online: September 15, 2017
Abstract
AIM

To investigate matrix metalloproteinase-11 (MMP-11) expression in adipose tissue dysfunction, using in vitro and in vivo models of insulin resistance.

METHODS

Culture of mouse 3T3-L1 preadipocytes were induced to differentiation into mature 3T3-L1 adipocytes. Cellular insulin resistance was induced by treating differentiated cultured adipocytes with hypoxia and/or tumor necrosis factor (TNF)-α, and transcriptional changes were analyzed in each condition thereafter. For the in vivo studies, MMP-11 expression levels were measured in white adipose tissue (WAT) from C57BL/6J mice that underwent low fat diet or high-fat feeding in order to induce obesity and obesity-related insulin resistance. Statistical analysis was carried out with GraphPad Prism Software.

RESULTS

MMP-11 mRNA expression levels were significantly higher in insulin resistant 3T3-L1 adipocytes compared to control cells (1.46 ± 0.49 vs 0.83 ± 0.21, respectively; P < 0.00036). The increase in MMP-11 expression was observed even in the presence of TNF-α alone (3.79 ± 1.11 vs 1 ± 0.17, P < 0.01) or hypoxia alone (1.79 ± 0.7 vs 0.88 ± 0.1, P < 0.00023). The results obtained in in vitro experiments were confirmed in the in vivo model of insulin resistance. In particular, MMP-11 mRNA was upregulated in WAT from obese mice compared to lean mice (5.5 ± 2.8 vs 1.1 ± 0.7, respectively; P < 3.72E-08). The increase in MMP-11 levels in obese mice was accompanied by the increase in typical markers of fibrosis, such as collagen type VI alpha 3 (Col6α3), and fibroblast-specific protein 1.

CONCLUSION

Our results indicate that dysregulation of MMP-11 expression is an early process in the adipose tissue dysfunction, which leads to obesity and obesity-related insulin resistance.

Keywords: Metalloproteinase-11, Insulin resistance, Type 2 diabetes, Fibrosis, Hypoxia, Tumor necrosis factor-α, Inflammation

Core tip: 3T3-L1 mature adipocytes are widely used as a cellular model of obesity. We treated 3T3-L1 adipocytes with tumor necrosis factor-α and/or hypoxia for 24 h to induce insulin resistance. Matrix metalloproteinase-11 (MMP-11) expression levels were upregulated in insulin resistant adipocytes, as compared to untreated control cells. This observation was confirmed in vivo, in white adipose tissue from insulin-resistant obese mice. Therefore, our results suggest that MMP-11 could play a role in the dysfunction of adipose tissue, which leads to insulin resistance and type 2 diabetes. Further work is necessary to understand better the functional role of MMP-11 in this context.