Matrix metalloproteinase-9 is increased in obese subjects and decreases in response to pioglitazone.
BACKGROUND
The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans.


OBJECTIVE
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.


METHODS
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.


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.


CONCLUSIONS
These data indicate that MMP-9 is elevated in insulin resistance and is reduced by pioglitazone.
Unal
Resat
R
Division of Endocrinology, Department of Medicine, University of Kentucky, and Barnstable Brown Diabetes and Obesity Center, Lexington, Kentucky 40536, USA.
Yao-Borengasser
Aiwei
A
Varma
Vijayalakshmi
V
Rasouli
Neda
N
Labbate
Craig
C
Kern
Philip A
PA
Ranganathan
Gouri
G
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000273:Adipose Tissue / Q000201:enzymology; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D015992:Body Mass Index; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D009765:Obesity / Q000201:enzymology*; D009841:Oligonucleotides / Q000378:metabolism; D000077205:Pioglitazone; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014162:Transfection; D055815:Young Adult
D007004:Hypoglycemic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009841:Oligonucleotides; D045162:Thiazolidinediones; D012313:RNA; D051571:Protein Kinase C-alpha; D020780:Matrix Metalloproteinase 9; D000077205:Pioglitazone
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