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: 4.13).
11/2006; 70(4):1164-73. 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/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.
Available from: Nicolas Lanthier
- "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  . 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 . "
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ABSTRACT: In the context of obesity, white adipocyte hypertrophy and adipose tissue macrophage infiltration result in the production of pro-inflammatory adipocytokines inducing insulin resistance locally but also in distant organs and contributing to low grade inflammatory status associated with the metabolic syndrome. Visceral adipose tissue is believed to play a prominent role. Brown and beige adipose tissues are capable of energy dissipation, but also of cytokine production and their role in dysmetabolic syndrome is emerging. This review focuses on metabolic and inflammatory changes in these adipose depots and contribution to metabolic syndrome. Also we will review surgical and pharmacological procedures to target adiposity as therapeutic interventions to treat obesity-associated disorders.
Available from: Lenka Rossmeislová
- "BAs were shown to regulate adipocyte functions through the activation of nuclear farnesoid X receptor (FXR) and specific G protein-coupled membrane surface receptor TGR5 [11,12]. In 3T3-L1 cells, FXR cooperates with PPARγ and in addition to that it stimulates adipogenesis also through inhibition of Wnt pathway [11,13].In brown adipocytes, TGR5 pathway regulates energy expenditure through the induction of mitochondrial uncoupling protein (UCP1) expression . However, these findings have not yet been confirmed in humans and effects of BAs on properties of human preadipocytes, resp. "
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ABSTRACT: Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.
Available from: Luciano Adorini
- "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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ABSTRACT: Insulin resistance is the putative key underlying mechanism linking adipose tissue (AT) dysfunction, and liver inflammation and steatosis in metabolic syndrome (MetS). We have recently demonstrated that the selective FXR agonist obeticholic acid (OCA) ameliorates insulin-resistance and the metabolic profile with a marked reduction of visceral AT (VAT) in a high-fat diet (HFD)-induced rabbit model of MetS. These effect were mediated by activation of FXR, since treatment with the selective TGR5 agonist, INT-777, was not able to ameliorate metabolic parameters. We now report the effects of in vivo OCA dosing on liver, VAT, and the adipogenic capacity of isolated VAT preadipocytes (rPADs) from rabbits on HFD compared to control diet. VAT and liver were studied by immunohistochemistry, Western blot, and RT-PCR. rPADs were exposed to a differentiating mixture (DIM) to evaluate adipogenesis. Adipocyte size, hypoxia, expression of perilipin and cytosolic insulin-regulated glucose transporter GLUT4 were significantly increased in HFD VAT and normalized by OCA. In HFD liver, expression of steatosis and inflammation markers was increased in HFD liver and normalized by OCA. HFD rPADs were less sensitive to insulin, as demonstrated by decreased insulin-induced glucose uptake, triglyceride synthesis, and adipogenetic capacity, as well as by impaired fusion of lipid droplets. OCA treatment preserved all the aforementioned functions. In conclusion, OCA dosing in a MetS rabbit model ameliorates liver and VAT functions. This could reflect the ability of OCA to restore insulin sensitivity in AT unable to finalize its storage function, counteracting MetS-induced metabolic alterations and pathological AT deposition.
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