The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways.
The bile acid receptor farnesoid X receptor (FXR) is expressed in adipose tissue, but its function remains poorly defined. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipocyte differentiation and function. The aim of this study was to analyze the role of FXR in adipocyte function and to assess whether it modulates PPARγ action. Therefore, we tested the responsiveness of FXR-deficient mice (FXR(-/-)) and cells to the PPARγ activator rosiglitazone. Our results show that genetically obese FXR(-/-)/ob/ob mice displayed a resistance to rosiglitazone treatment. In vitro, rosiglitazone treatment did not induce normal adipocyte differentiation and lipid droplet formation in FXR(-/-) mouse embryonic fibroblasts (MEFs) and preadipocytes. Moreover, FXR(-/-) MEFs displayed both an increased lipolysis and a decreased de novo lipogenesis, resulting in reduced intracellular triglyceride content, even upon PPARγ activation. Retroviral-mediated FXR re-expression in FXR(-/-) MEFs restored the induction of adipogenic marker genes during rosiglitazone-forced adipocyte differentiation. The expression of Wnt/β-catenin pathway and target genes was increased in FXR(-/-) adipose tissue and MEFs. Moreover, the expression of several endogenous inhibitors of this pathway was decreased early during the adipocyte differentiation of FXR(-/-) MEFs. These findings demonstrate that FXR regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARγ and Wnt/β-catenin pathways.
Abdelkarim
Mouaadh
M
Université Lille Nord de France, F-59000 Lille, France.
Caron
Sandrine
S
Duhem
Christian
C
Prawitt
Janne
J
Dumont
Julie
J
Lucas
Anthony
A
Bouchaert
Emmanuel
E
Briand
Olivier
O
Brozek
John
J
Kuipers
Folkert
F
Fievet
Catherine
C
Cariou
Bertrand
B
Staels
Bart
B
D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D004351:Drug Resistance; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D027261:Fusion Regulatory Protein-1; D020869:Gene Expression Profiling; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D015415:Biomarkers; D027261:Fusion Regulatory Protein-1; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D051153:Wnt Proteins; D051176:beta Catenin; D000099150:Receptor, Farnesoid X-Activated