Association of MMP-8 with obesity, smoking and insulin resistance.
BACKGROUND
Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors.


METHODS
We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE.


RESULTS
We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001.


CONCLUSIONS
Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.
Department of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland.|Clinicum, University of Helsinki, Helsinki, Finland.
Anneli
A
Lauhio
Department of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland.|Clinicum, University of Helsinki, Helsinki, Finland.|Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland.
Esa
E
Färkkilä
Clinicum, University of Helsinki, Helsinki, Finland.|Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland.
Kirsi H
KH
Pietiläinen
Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
Pirjo
P
Åström
Department of Periodontology, Institute of Dentistry, University of Helsinki, Helsinki, Finland.
Alina
A
Winkelmann
Department of Periodontology, Institute of Dentistry, University of Helsinki, Helsinki, Finland.
Taina
T
Tervahartiala
Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
Emma
E
Pirilä
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
Aila
A
Rissanen
FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Department of Public Health, University of Helsinki, Helsinki, Finland.|Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Jaakko
J
Kaprio
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland.|Department of Periodontology, Institute of Dentistry, University of Helsinki, Helsinki, Finland.|Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
Timo A
TA
Sorsa
Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.|Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.|Department of Oral Pathology, Institute of Dentistry, University of Helsinki, Helsinki, Finland.|Helsinki University Central Hospital, Helsinki, Finland.
Tuula
T
Salo
D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D016022:Case-Control Studies; D004151:Dipeptides / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000097:blood; D020784:Matrix Metalloproteinase 8 / Q000097:blood* / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009765:Obesity / Q000097:blood*; D050177:Overweight / Q000097:blood; D011972:Receptor, Insulin / Q000378:metabolism; D012907:Smoking / Q000097:blood*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic; D055815:Young Adult
D015703:Antigens, CD; D004151:Dipeptides; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C435941:INSR protein, human; D011972:Receptor, Insulin; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C119203:ilomastat; D004318:Doxycycline
Insulin resistance; MMP-8; MMP-8 inhibitor; obesity; smoking; therapy target