Matrix metalloproteinase-9 is increased in obese subjects and decreases in response to pioglitazone

The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans. The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissu...

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Published in:The journal of clinical endocrinology and metabolism Vol. 95; no. 6; p. 2993
Main Authors: Unal, Resat, Yao-Borengasser, Aiwei, Varma, Vijayalakshmi, Rasouli, Neda, Labbate, Craig, Kern, Philip A, Ranganathan, Gouri
Format: Journal Article
Language:English
Published: United States 01.06.2010
Subjects:
Adipocytes - drug effects
Adipocytes - enzymology
Adipose Tissue - enzymology
Adult
Aged
Blotting, Western
Body Mass Index
Cells, Cultured
Coculture Techniques
Female
Humans
Hypoglycemic Agents - therapeutic use
Insulin Resistance
Male
Matrix Metalloproteinase 9 - biosynthesis
Matrix Metalloproteinase 9 - metabolism
Matrix Metalloproteinase Inhibitors
Middle Aged
Obesity - enzymology
Oligonucleotides - metabolism
Pioglitazone
Protein Kinase C-alpha - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA - biosynthesis
RNA - genetics
Stromal Cells - drug effects
Stromal Cells - enzymology
Th1 Cells - drug effects
Th1 Cells - enzymology
Thiazolidinediones - therapeutic use
Transfection
Young Adult
ISSN:1945-7197, 1945-7197
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Summary:The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans. 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. 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 C alpha antisense oligomers, and MMP-9 levels were examined. 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. These data indicate that MMP-9 is elevated in insulin resistance and is reduced by pioglitazone.
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ISSN:1945-7197
1945-7197
DOI:10.1210/jc.2009-2623