RT Journal Article
SR Electronic
T1 The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1164
OP 1173
DO 10.1124/mol.106.023820
VO 70
IS 4
A1 Giovanni Rizzo
A1 Moises Disante
A1 Andrea Mencarelli
A1 Barbara Renga
A1 Antimo Gioiello
A1 Roberto Pellicciari
A1 Stefano Fiorucci
YR 2006
UL http://molpharm.aspetjournals.org/content/70/4/1164.abstract
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