Article

The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo

Department of Clinical and Experimental Medicine, Università degli Studi di Perugia, Perugia, Umbria, Italy
Molecular Pharmacology (Impact Factor: 4.12). 11/2006; 70(4):1164-73. DOI: 10.1124/mol.106.023820
Source: PubMed

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/EBPalpha, and PPARgamma2 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 PPARgamma antagonist, indicating that FXR modulates adipocyte-related genes by PPARgamma-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.

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    • "It is also expressed, although in lower levels, in the adipose tissue. In vitro data evidenced that a FXR agonist was able to induce preadipocyte differentiation [86] [89]. The selective FXR agonist obeticholic acid causes a reduction in VAT adipocytes size, a mechanisms that could participate to the insulin sensitizing effect of this molecule [90]. "
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    • "Our results indicate that the beneficial effect of OCA on HFD-induced insulin resistance is mediated by the specific activation of FXR, rather than TGR5, at both VAT and hepatic levels. Indeed, we found that i) the treatment of the HFD rabbits with the selective TGR5 agonist INT-777 does not affect HFD-induced glucose intolerance and increased fasting glycemia; ii) the expression of TGR5 in the liver and VAT is markedly lower compared to FXR; iii) the expression of FXR primary response genes, SHP and CYP7A1, is respectively upregulated and downregulated by OCA treatment, as expected following FXR activation (Rizzo et al. 2006). These data, together with the known 200-fold greater agonistic activity of OCA for FXR when compared with TGR5 (Rizzo et al. 2010), support the view that all the observed OCA effects on HFD-induced MetS are selectively mediated by FXR activation. "
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    • "All PPAR isotypes form a heterodimeric complex with the retinoid X receptor (RXR), and the complex binds to the PPAR response element, which functions as the central regulator of cellular differentiation [5], apoptosis [6], inflammatory responses [7] [8], lipid metabolism, and metabolic disease [9]. Also, the farnesoid X receptor (FXR) is involved in adipogenesis , adipocyte differentiation, and lipid storage, increasing adiponectin through a mechanism partially mediated by PPAR-gamma (PPAR-γ) [10] [11]. PPAR-γ is expressed generally in multiple tissues, such as lung, breast, ovary, placenta, and colon. "
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