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Journal of Lipid Research, Vol. 47, 2080-2088, September 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
Patient-Oriented Research |
Pioglitazone induces apoptosis of macrophages in human adipose tissue
* The Central Arkansas Veterans Healthcare System, and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
The Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205
The Department of Pediatrics, Division of Neonatology, and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205
** Pediatric Endocrinology, Department of Pediatrics, University of Ulm, 89075 Ulm, Germany
Published, JLR Papers in Press, June 23, 2006.
1 To whom correspondence should be addressed. e-mail: KernPhilipA{at}uams.edu
ABSTRACT
Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor 
(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 terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (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 treatment. 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 piolgitazone. These findings indicate that PPAR has distinct functions in different cell types in WAT, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPAR activation.
Supplementary key words PPAR • diabetes • metabolic syndrome • insulin resistance
Abbreviations: IGT, impaired glucose tolerance; IL-6, interleukin-6; PPAR, peroxisome proliferator-activated receptor; SGBS, Simpson-Golabi-Behmel syndrome; TNF-
, tumor necrosis factor-; TPA, tetradecanoylphorbol-13-acetate; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; TZD, thiazolidinedione; WAT, white adipose tissue
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