The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo

• Published in: Molecular pharmacology 2006-10, Vol.70 (4), p.1164-1173
• Main Authors: Rizzo, Giovanni, Disante, Moises, Mencarelli, Andrea, Renga, Barbara, Gioiello, Antimo, Pellicciari, Roberto, Fiorucci, Stefano
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - metabolism; Adipocytes - physiology; Adipogenesis; Animals; Cell Differentiation; Cell Line; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Gene Expression; Glucose - pharmacokinetics; Humans; Ligands; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxisome Proliferator-Activated Receptors - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Transfection
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.106.023820

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.