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Tissue Distribution and Regulation of Plasminogen Activator Inhibitor-1 in Obese Mice

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Abstract

Background

Although elevated plasminogen activator inhibitor-1 (PAI-1) is associated with obesity and may be a risk factor for cardiovascular disease, the mechanism(s) that lead to this elevation, and the tissue/cellular origins of this increase, remain to be defined. In this report, we have addressed these questions using genetically obese mice (ob/ob) and their lean counterparts (+/?).

Materials and Methods

PAI-1 activity and antigen levels were determined using a tissue-type plasminogen activator (t-PA) binding assay and Western blotting. The concentration of PAI-1 mRNA in tissues was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and the cellular localization of PAI-1 was evaluated using in situ hybridization, immunohistochemistry, and cell fractionation.

Results

PAI-1 activity was approximately 4-fold higher in plasma from ob/ob mice than in that obtained from their lean counterparts, and this difference increased further with age (i.e., 6-fold at 3 months). PAI-1 mRNA levels were elevated 4- to 5-fold in the adipose tissues of obese mice, and these differences in mRNA also increased with age. The elevated PAI-1 mRNA in the adipose tissues of obese mice was localized to mature adipocytes as well as to vascular smooth muscle cells and occasional endothelial cells. Obesity is often associated with hyperinsulinemia, and acute injection of insulin into lean mice increased PAI-1 mRNA 6- to 8-fold in the epididymal fat in cells that morphologically resembled adipocytes. Insulin did not increase PAI-1 in large vessel endothelial or smooth muscle cells. The adipocyte response to insulin was confirmed in cell culture studies where PAI-1 synthesis by mature 3T3-L1 adipocytes was increased 5- to 6-fold by insulin.

Conclusions

Our results suggest that elevated PAI-1 associated with obesity may result in part from insulin-induced induction of PAI-1 specifically by adipocytes within the fat itself.

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Acknowledgments

The authors thank T. Thinnes and M. Pandey for their technical assistance. In addition we wish to thank M. McRae for her expert secretarial skills. This work was supported by National Institutes of Health Grant HL 47819 to DJL.

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Authors and Affiliations

  1. Department of Vascular Biology, The Scripps Research Institute, 10666 N. Torrey Pines Road, VB-3, La Jolla, California, 92037, USA

    F. Samad & D. J. Loskutoff

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  1. F. Samad
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  2. D. J. Loskutoff
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This work was presented in part at the XIIth International Congress on Fibrinolysis, September 1994, in Leuven, Belgium.

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Samad, F., Loskutoff, D.J. Tissue Distribution and Regulation of Plasminogen Activator Inhibitor-1 in Obese Mice. Mol Med 2, 568–582 (1996). https://doi.org/10.1007/BF03401641

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