Research ArticleMetabolic Disease

Adipocyte-Derived Factors Potentiate Nutrient-Induced Production of Plasminogen Activator Inhibitor–1 by Macrophages

Science Translational Medicine  24 Feb 2010:
Vol. 2, Issue 20, pp. 20ra15
DOI: 10.1126/scitranslmed.3000292

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Deleterious Cytokines from Adipose Tissue

Obesity is bad for your metabolism. One possible contributor to obesity-induced diabetes and atherosclerosis is plasminogen activator inhibitor-1 or PAI-1, a hormone secreted from fat cells. PAI-1, a protease inhibitor and hemostatic agent, is correlated with cardiovascular events and atherosclerosis, and mice engineered without this hormone are protected from these diseases. Free fatty acids in blood, which are derived from the diet, are also correlated with PAI-1, with higher fatty acid concentrations resulting in more blood PAI-1.

Kishore et al. tested whether diet-derived free fatty acids cause increased PAI-1 production in human adipose tissue, focusing on macrophages, immune cells resident in fat that secrete PAI-1. By delivering free fatty acids directly to the bloodstream of their subjects, the authors elicited increased serum PAI-1 concentrations, as well as decreased glucose uptake into tissues. This increased PAI-1 in blood was accompanied by PAI-1 gene expression in macrophages from adipose tissue, although similar cells in the bloodstream did not respond in this way to the fatty acids. Suspecting that the fat cells surrounding the adipose tissue macrophages were somehow sensitizing the macrophages, the authors added adipocyte-conditioned medium to macrophages. This treatment augmented the response of the macrophages to fatty acids, boosting their production of PAI-1. Thus the adipose-tissue macrophages seemed to be uniquely stimulated by their surrounding environment to respond to free fatty acids by secreting the undesirable hormone PAI-1, which can increase propensity to cardiovascular disease.

Adipose tissue is gaining a reputation for being more than an inert fat depot. The results from this study by Kishore et al. reinforce this idea, suggesting that in humans adipose tissue delivers elevated concentrations of PAI-1 by creating a unique, local paracrine environment to promote its synthesis.


  • Citation: P. Kishore, W. Li, J. Tonelli, D.-E. Lee, S. Koppaka, K. Zhang, Y. Lin, S. Kehlenbrink, P. E. Scherer, M. Hawkins, Adipocyte-derived factors potentiate nutrient-induced production of plasminogen activator inhibitor–1 by macrophages. Sci. Transl. Med. 2, 20ra15 (2010).