Matrix Metalloproteinase-9 Is Increased in Obese Subjects and Decreases in Response to Pioglitazone

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 6; pp. 2993 - 3001
• Main Authors: Unal, Resat, Yao-Borengasser, Aiwei, Varma, Vijayalakshmi, Rasouli, Neda, Labbate, Craig, Kern, Philip A., Ranganathan, Gouri
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.06.2010; Copyright by The Endocrine Society; Endocrine Society; The Endocrine Society
• Subjects: Abdominal wall; Adipocytes; Adipocytes - drug effects; Adipocytes - enzymology; Adipose tissue; Adipose Tissue - enzymology; Adult; Aged; Biological and medical sciences; Biopsy; Blotting, Western; Body fat; Body Mass Index; Cells, Cultured; Coculture Techniques; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gelatinase B; Glucose; Glucose tolerance; Humans; Hypoglycemic Agents - therapeutic use; Insulin Resistance; Kinases; Macrophages; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Medical sciences; Metalloproteinase; Metformin; Middle Aged; mRNA; Obesity; Obesity - enzymology; Oligonucleotides - metabolism; Original; Pioglitazone; Protein kinase C; Protein Kinase C-alpha - metabolism; Research design; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA - genetics; Sensitivity analysis; Stromal Cells - drug effects; Stromal Cells - enzymology; Th1 Cells - drug effects; Th1 Cells - enzymology; Thiazolidinediones - therapeutic use; Transfection; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Young Adult; Human; Obesity; Nutrition; Enzyme; Pioglitazone; Nutrition disorder; Metalloendopeptidases; Metabolic diseases; Thiazolidinedione derivatives; Gelatinase B; Peptidases; Hypoglycemic agent; Hydrolases; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2009-2623

Context: The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans. Objectives: The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissue biopsies and study the mechanism of MMP-9 regulation by pioglitazone in adipocyte cultures. Research Design: 86 nondiabetic, weight-stable subjects between 21 and 66 yr of age were recruited in a university hospital research center setting. All subjects underwent a sc adipose tissue incisional biopsy from the lower abdominal wall and insulin sensitivity testing using a frequently sampled iv glucose tolerance test. Impaired glucose-tolerant subjects were randomized to receive metformin or pioglitazone for 10 wk. To study the mechanism of MMP-9 regulation in adipocytes, cells were treated with pioglitazone or protein kinase Cα antisense oligomers, and MMP-9 levels were examined. Results: There was a positive correlation between MMP-9 and body mass index (r = 0.40, P < 0.01) and negative correlation between MMP-9 and insulin sensitivity (r = −0.46, P < 0.001). The improvement in insulin sensitivity from pioglitazone resulted in a 52 ± 0.2% reduction in MMP-9 mRNA. Fractionation of adipose tissue indicated that MMP-9 was mostly in the stromal vascular fraction. Pioglitazone also decreased MMP-9 in 3T3-F442A adipocytes and THP1 macrophages. Coculture of adipocytes with macrophages augmented MMP-9 expression in adipocytes and pioglitazone decreased MMP-9 in both adipocytes and macrophages. Conclusion: These data indicate that MMP-9 is elevated in insulin resistance and is reduced by pioglitazone.MMP-9 is down-regulated by Pioglitazone, and this is likely mediated by a decrease in PKCα.