The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

Abstract

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.The farnesoid X receptor (FXR) 4 (NR1H4) is a nuclear receptor that is activated by bile acids (BAs) (1). A major physiological role of FXR is to protect liver cells from the deleterious effect of BA overload by decreasing their endogenous production and by accelerating BA biotransformation and excretion (1). In addition, the generation and characterization of FXR-deficient (FXR Ϫ/Ϫ ) mice has also established a critical role of FXR in lipid metabolism, since these mice display elevated serum levels of triglycerides and high density lipoprotein cholesterol (2). Recently, several studies have suggested that FXR might also regulate hepatic carbohydrate metabolism (3). The first indication came from the observation that hepatic FXR expression is reduced in several rodent models of diabetes (4). FXR expression also varies in mouse liver during nutritional changes, being increased during fasting and decreased upon refeeding (5, 6). Moreover, FXR activation by BAs or the synthetic nonsteroidal specific agonist GW4064 (7) modulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (3). However, conflicting data report either a positive (8) or a negative effect (9, 10) of BA and/or GW4064 on phosphoenolpyruvate...

The bile salt export pump

“…In the light of recent findings that bile saltmediated FXR signaling controls liver regeneration and may even control liver size [44], Bsep may move up to a key protein controlling many vital processes in liver. Furthermore, evidence that the bile acid sensor FXR is controlling glucose and lipid metabolism is rapidly accumulating [11,16,58]. Since FXR requires bile salt binding to act to control expression target genes, Bsep may, by controlling bile salt concentration in systemic circulation, become an important control element in body energy and lipid homeostasis.…”

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…6D, not only OPN expression was Ϸ3-fold higher in FXR Ϫ/Ϫ NKT cells in comparison to WT cells, but, while exposure of WT NKT cells to Con A resulted in a robust induction of OPN mRNA expression ( p Ͻ 0.05 vs untreated), OPN expression was boosted up to 7-fold in FXR Ϫ/Ϫ NKT cells ( p Ͻ 0.01 vs WT cells treated with Con A). To gain insight on the molecular mechanisms involved in OPN regulation by FXR in NKT cells, additional experiments were conducted using a NKT cell hybridoma (the murine V␣14 invt TCR ϩ CD1d-specific T-T hybridoma DN32.D3 (39). By qualitative RT-PCR, Western blot analysis and real-time qRT-PCR, we found that DN32.D3 cells, nonactivated by Con A, express FXR along with the FXR-regulated gene SHP (Fig.…”

“…Thus, there is circumstantial evidence to link the activity of FXR to the regulation of bile acid synthesis from cholesterol, providing a link between nutrient absorption and regulation of key steps in the intermediate metabolism. In addition, because bile acids might be toxic for the liver, activation of FXR by natural and synthetic ligands has been shown to prevent bile acid-induced liver toxicity in a variety of rodent models (33)(34)(35)(36)(37)(38)(39). The homeostatic function of FXR in the liver is highlighted by the demonstration that mice harboring a disrupted FXR (FXR Ϫ/Ϫ ) develop spontaneously an array of hepatocellular abnormalities including adenomas and carcinomas.…”

Obesity diabetes and the role of bile acids in metabolism

“…Bile acid activation of FXR in the intestine stimulates synthesis of fibroblast growth factor (FGF) 15/19, which is involved in lipid and carbohydrate metabolism. FXR, through its downstream effect on FGF, is important in maintaining normolipidaemia, normoglycaemia, and bile acid homeostasis [9,10] . FGF inhibits CYP7A1 expression, the first step in the conversion of cholesterol to bile acids.…”