Thiazolidinedione-induced activation of the transcription factor peroxisome proliferator-activated receptor gamma in cells adjacent to the murine skeletal muscle: implications for fibroblast functions

Nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) is th e target of antidiabetogenic thiazolidinediones (TZD). However, recent stud ies failed to show that TZD has an effect in vitro on insulin-regulated glu cose uptake in skeletal muscles, the major site of glucose disposal. The po tential effects of TZD on cells adjacent to skeletal muscles are not well c haracterized but may be involved in TZD's actions. Hence, we studied these cells from mice treated with the carrier and with the TZD ciglitazone (9 nm ol/g body weight). The cells were typified by lipid enrichment (floating ad ipocytes and macrophages), by the ectopic expression of cellular fibronecti n (fibroblasts), fibronectin and PPAR gamma (preadipocytes), PPAR gamma and CD11b/Mac-1 (active macrophages) as revealed by flow cytometry and immunob lotting. The glucose transporter 4 proteins (GLUT4) and the uptake of gluco se and long-chain fatty acids (LCFA) were determined flow cytometrically us ing fluorescent derivatives of glucose (NBDG) and LCFA (C16-Bodipy). The ex pression of tumor necrosis factor alpha (TNF alpha) in CD11b/Mac-1-positive and CD11b/Mac-1-negative cells separated by magnetic immunobeads was analy zed. The results showed that TZD treatment upregulated GLUT4 expression, an d increased insulin-regulated NBDG uptake and C16-Bodipy binding and influx , at the same time as increasing the quantity of PPAR gamma-expressing fibr oblasts; this indicates the development of the preadipocyte phenotype. In c ontrast, TZD lowered the number of adipocytes (0.6-fold compared to the car rier-treated control) perhaps through an action of TNF alpha from CD11b- an d PPAR gamma-expressing macrophages. The data suggest that the regulatory e ffects of TZD on energy homeostasis involve two major targets: the PPAR gam ma-positive fibroblasts whose adipogenic program is promoted, and CD11b-PPA R gamma-expressing macrophages which become cytotoxic and fibrogenic becaus e of the effects of TNF alpha on neighboring adipocytes and fibroblasts, re spectively.