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Research ArticleArticle

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

Giovanni Rizzo, Moises Disante, Andrea Mencarelli, Barbara Renga, Antimo Gioiello, Roberto Pellicciari and Stefano Fiorucci
Molecular Pharmacology October 2006, 70 (4) 1164-1173; DOI: https://doi.org/10.1124/mol.106.023820
Giovanni Rizzo
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Moises Disante
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Andrea Mencarelli
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Barbara Renga
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Antimo Gioiello
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Roberto Pellicciari
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Stefano Fiorucci
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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 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.

Footnotes

  • ABBREVIATIONS: FXR, farnesoid X receptor; RXR, retinoid X receptor; SHP, small heterodimer partner; INT-747, 6-ethyl chenodeoxycholic acid; CDCA, 6-ethyl chenodeoxycholic acid; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; DIM, differentiation mixture; IBMX, 3-iso-butyl-1-methylxanthine; PCR, polymerase chain reaction; qRT-PCR, quantitative real-time PCR; CT, cycle threshold (the cycle number at which each PCR reaction reaches a predetermined fluorescence threshold); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; C/EBP, CAAT/enhancer-binding protein; PPAR, peroxisome proliferator-activated receptor; FABP, fatty acid binding protein; SREBP-1c, sterol-regulatory element binding protein-1c; TNFα, tumor necrosis factor α; GW9662, 2-chloro-5-nitro-N-phenylbenzamide.

    • Received February 25, 2006.
    • Accepted June 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (4)
Molecular Pharmacology
Vol. 70, Issue 4
1 Oct 2006
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Research ArticleArticle

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

Giovanni Rizzo, Moises Disante, Andrea Mencarelli, Barbara Renga, Antimo Gioiello, Roberto Pellicciari and Stefano Fiorucci
Molecular Pharmacology October 1, 2006, 70 (4) 1164-1173; DOI: https://doi.org/10.1124/mol.106.023820

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Research ArticleArticle

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

Giovanni Rizzo, Moises Disante, Andrea Mencarelli, Barbara Renga, Antimo Gioiello, Roberto Pellicciari and Stefano Fiorucci
Molecular Pharmacology October 1, 2006, 70 (4) 1164-1173; DOI: https://doi.org/10.1124/mol.106.023820
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