Pioglitazone reduces inflammatory responses of human adipocytes to factors secreted by monocytes/macrophages

• Published in: American journal of physiology: endocrinology and metabolism Vol. 296; no. 5; pp. E1076 - E1084
• Main Authors: Permana, Paska A, Zhang, Weiyang, Wabitsch, Martin, Fischer-Posovszky, Pamela, Duckworth, William C, Reaven, Peter D
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2009
• Subjects: Adhesion; Adipocytes - drug effects; Adipocytes - immunology; Adipokines - biosynthesis; Adipokines - genetics; Adipose tissue; Cell adhesion & migration; Cells; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Enzyme-Linked Immunosorbent Assay; Gene expression; Humans; Hypoglycemic Agents - pharmacology; Infiltration; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Intra-Abdominal Fat - drug effects; Intra-Abdominal Fat - immunology; Intra-Abdominal Fat - pathology; Macrophages - drug effects; Macrophages - immunology; Macrophages - secretion; Male; Middle Aged; Molecules; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Subcutaneous Fat - drug effects; Subcutaneous Fat - immunology; Subcutaneous Fat - pathology; Thiazolidinediones - pharmacology; Tissues; U937 Cells; Vascular Cell Adhesion Molecule-1 - biosynthesis; Vascular Cell Adhesion Molecule-1 - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.91013.2008

1 Research Service and 3 Department of Medicine, Section of Metabolism, Endocrinology, and Nutrition, Phoenix Veterans Affairs Health Care System, Phoenix, Arizona; and 2 Division of Pediatric Endocrinology and Diabetes, University of Ulm, Ulm, Germany Submitted 19 December 2008 ; accepted in final form 19 February 2009 Infiltration of monocyte-derived macrophages into adipose tissue may contribute to tissue and systemic inflammation and insulin resistance. We hypothesized that pioglitazone (Pio) could specifically reduce the inflammatory response of adipocytes to factors released by monocytes/macrophages. We show that macrophage factors (M -factors) greatly increase expression levels of proinflammatory adipokines, chemokines, and adhesion molecules in human subcutaneous and visceral adipose tissue (SAT and VAT) as well as in adipocytes (up to several hundredfold of control). Compared with SAT, VAT showed enhanced basal and M -factor-induced inflammatory responses. M -factors also induced greater lipolysis in adipocytes, as assessed by concentrations of glycerol released from the cells (196 ± 13 vs. 56 ± 7 µM in control, P < 0.05). Pretreatment of adipose tissue or adipocytes with Pio reduced these responses to M -factors (by 13–86%, P < 0.05) and prevented M -factor suppression of adiponectin expression. Furthermore, Pio pretreatment of adipocytes and macrophages tended to further reduce inflammatory responses of adipocytes to M -factors and monocyte adhesion to M -factor-activated adipocytes. In support of these in vitro data, media conditioned by monocytes isolated from impaired glucose-tolerant subjects treated with Pio (compared with placebo) induced release of lower concentrations of proinflammatory adipokines and glycerol (100 ± 7 vs. 150 ± 15 µM, P < 0.05) from adipocytes. In summary, Pio decreases inflammatory responses in adipose tissue/cells induced by monocytes/macrophages by acting on either or both cell types. These beneficial effects of Pio may attenuate proinflammatory responses resulting from monocyte/macrophage infiltration into adipose tissue and suppress tissue inflammation resulting from the interaction between both cell types. subcutaneous; visceral; adipose; cross talk; inflammation Address for reprint requests and other correspondence: P. A. Permana, CS/111E, Phoenix Veterans Affairs Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85012-1892 (e-mail: Paska.Permana{at}va.gov )