The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo
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.
- SourceAvailable from: Nicolas Lanthier
[Show abstract] [Hide abstract]
- "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 . "
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.Baillière' s Best Practice and Research in Clinical Gastroenterology 08/2014; 28(4). DOI:10.1016/j.bpg.2014.07.002 · 3.28 Impact Factor
[Show abstract] [Hide abstract]
- "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. "
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.Journal of Endocrinology 06/2013; 218(2). DOI:10.1530/JOE-13-0109 · 3.59 Impact Factor
[Show abstract] [Hide abstract]
- "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 , apoptosis , inflammatory responses  , lipid metabolism, and metabolic disease . 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)  . PPAR-γ is expressed generally in multiple tissues, such as lung, breast, ovary, placenta, and colon. "
ABSTRACT: A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.PPAR Research 11/2012; 2012:318613. DOI:10.1155/2012/318613 · 1.64 Impact Factor