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First published on June 15, 2006; DOI: 10.1124/mol.106.023820

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Received for publication February 27, 2006.
Revised June 15, 2006.
Accepted for publication June 15, 2006.

FXR Promotes Adipocyte Differentiation and regulates adipose cell function in vivo

Giovanni Rizzo 1, Moises Disante 1, Andrea Mencarelli 1, Barbara Renga 1, Antimo Gioiello 1, Roberto Pellicciari 1, Stefano Fiorucci 1*

1 University of Perugia

* Address correspondence to: E-mail: fiorucci{at}unipg.it

Abstract

ABSTRACT 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 associated with adipogenesis including 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). Here we 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 associates with induction of aP2, C\EBP{alpha} and PPAR{gamma}2 mRNAs along with other adipocyte-related genes. This effect was reversed by guggulsterone, a FXR antagonist, and by GW9662 (2-Chloro-5-nitro-N-phenylbenzamide) a selective PPAR{gamma} antagonist, and lost in FXR-/- mice, indicating that FXR activates PPAR{gamma}-dependent and independent pathways. 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 signalling.


Key words: Insulin, PPARs, Regulation - transcriptional, Cholesterol metabolism/lipoproteins


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