title: Pioglitazone induces apoptosis of macrophages in human adipose tissue.
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 gamma (PPARgamma) 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 PPARgamma 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 PPARgamma has distinct functions in different cell types in WAT, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPARgamma activation.
authors.affiliation: The Central Arkansas Veterans Healthcare System, and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bodles
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Varma
authors.forename: Aiwei
authors.initials: A
authors.lastname: Yao-Borengasser
authors.forename: Bounleut
authors.initials: B
authors.lastname: Phanavanh
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Peterson
authors.forename: Robert E
authors.initials: RE
authors.lastname: McGehee
authors.forename: Neda
authors.initials: N
authors.lastname: Rasouli
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kern
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000097382:CD68 Molecule
chemical_list: D000813:Anilides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018955:CD36 Antigens; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D000077205:Pioglitazone; D045162:Thiazolidinediones; C457499:2-chloro-5-nitrobenzanilide; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C505407:CASP3 protein, human; C506433:CASP9 protein, human