The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice.
The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes.
Cariou
Bertrand
B
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, F-59019, France.
van Harmelen
Kirsten
K
Duran-Sandoval
Daniel
D
van Dijk
Theo H
TH
Grefhorst
Aldo
A
Abdelkarim
Mouaadh
M
Caron
Sandrine
S
Torpier
Gérard
G
Fruchart
Jean-Charles
JC
Gonzalez
Frank J
FJ
Kuipers
Folkert
F
Staels
Bart
B
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006720:Homozygote; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D005947:Glucose; D007328:Insulin; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064