PT - JOURNAL ARTICLE AU - Giovanni Rizzo AU - Moises Disante AU - Andrea Mencarelli AU - Barbara Renga AU - Antimo Gioiello AU - Roberto Pellicciari AU - Stefano Fiorucci TI - The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo AID - 10.1124/mol.106.023820 DP - 2006 Oct 01 TA - Molecular Pharmacology PG - 1164--1173 VI - 70 IP - 4 4099 - http://molpharm.aspetjournals.org/content/70/4/1164.short 4100 - http://molpharm.aspetjournals.org/content/70/4/1164.full SO - Mol Pharmacol2006 Oct 01; 70 AB - The differentiation of a preadipocyte into a mature adipocyte is a highly regulated process that requires a scripted program of transcriptional events leading to changes in gene expression. Several genes are associated with adipogenesis, including the CAAT/enhancer-binding protein (C/EBPs) and peroxisome proliferator-activated receptor (PPAR) families of transcription factors. In this study, we have investigated the role of the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, in regulating adipogenesis in a preadipocyte cell line (3T3-L1 cells). Our results show that FXR is expressed in the white adipose tissue of adult mice and in differentiated 3T3-L1 cells but not in undifferentiated preadipocytes. Exposure of 3T3-L1 cells to INT-747 (6-ethyl cheno-deoxycholic acid), a potent and selective FXR ligand, increases preadipocyte differentiation induced by a differentiating mixture containing insulin. Augmentation of differentiating mixture-induced differentiation of 3T3-L1 cells by INT-747 associated with induction of aP2, C/EBPα, and PPARγ2 mRNAs along with other adipocyte-related genes. This effect was reversed by guggulsterone, an FXR antagonist, and partially reverted by GW9662 (2-chloro-5-nitro-N-phenylbenzamide), a selective PPARγ antagonist, indicating that FXR modulates adipocyte-related genes by PPARγ-dependent and -independent pathways. Regulation of adipocyte-related genes by INT-747 was lost in FXR-/- mice, indicating that modulation of these genes by INT-747 requires an intact FXR. In addition, INT-747 enhances both insulin-induced serine phosphorylation of Akt and glucose uptake by 3T3-L1 cells. Taken together, these results suggest that activation of FXR plays a critical role in regulating adipogenesis and insulin signaling. The American Society for Pharmacology and Experimental Therapeutics