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Papers In Press, published online ahead of print June 23, 2006
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Medicine/Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
Corresponding Author: kernphilipa{at}uams.edu
Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue. Previously, we demonstrated that the treatment of impaired glucose tolerant (IGT) subjects with the PPAR agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with TUNEL staining. TUNEL positive cells were identified and there was a significant 42% increase in TUNEL positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody demonstrated that most of the TUNEL positive cells were macrophages. To determine whether macrophage apoptosis was a direct or indirect effect of pioglitazone treatment, human THP1 cells were treated with pioglitazone in vitro, demonstrating increased TUNEL staining in a dose- and time-dependent manner. Furthermore, the appearance of the active proteolytic subunits of caspase-3 and caspase-9 were detected in cell lysate from THP1 cells and also increased in a dose- and time-dependent manner following pioglitazone. Pretreatment with a PPAR inhibitor, GW9662, prevented pioglitazone induction of the apoptotic pathway in THP1 cells. Differentiated human adipocytes did not show any significant increase in apoptosis after treatment in vitro with pioglitazone. These findings indicate that PPAR has distinct functions in different cell types in white adipose tissue, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPAR activation.
Accepted on June 23, 2006
Pioglitazone induces apoptosis of macrophages in human adipose tissue
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