title: 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.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Via E dal Pozzo, 06122 Perugia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Moises
authors.initials: M
authors.lastname: Disante
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000502:physiology*; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D005947:Glucose / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D005947:Glucose; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid