Farnesoid X receptor is essential for normal glucose homeostasis
Ke Ma, … , Lawrence Chan, David D. Moore
Ke Ma, … , Lawrence Chan, David D. Moore
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1102-1109. https://doi.org/10.1172/JCI25604.
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Research Article Endocrinology

Farnesoid X receptor is essential for normal glucose homeostasis

Abstract

The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In FXR–/– skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR–/– mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR–/– and small heterodimer partner–null (SHP–/–) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.

Authors

Ke Ma, Pradip K. Saha, Lawrence Chan, David D. Moore

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Figure 6

Effects of FXR agonists.

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Effects of FXR agonists. Expression of genes involved in gluconeogenesis...
Expression of genes involved in gluconeogenesis and glucose and triglyceride levels, which were measured after a 1% CA diet for 5 days. Glucose and triglyceride levels were measured at fed state from 6–7 mice per group and RNA from each group was pooled from 3–4 mice after overnight fasting. (A) Suppression of genes involved in gluconeogenesis by CA feeding was observed in WT but not FXR–/– mice. FOXO1, forkhead transcription factor FOXO1. (B) Effect of CA diet on glycolytic genes. GK, glucokinase; PYC, pyruvate carboxylase; PYK, pyruvate kinase. (C) Reduced serum glucose was observed in CA-fed WT mice. (D) Reduced triglyceride levels were seen in CA-fed WT mice. (E) SHP was required for suppressed expression of gluconeogenic genes in response to CA feeding. (F) Plasma glucose levels in fasted and fed WT and SHP–/– mice (n = 8 per group). **P < 0.01 versus control diet; *P < 0.05, #P < 0.01 versus WT.