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Endocrinology. 2015 Apr;156(4):1263-71. doi: 10.1210/en.2014-1751. Epub 2015 Jan 19.

Role of FXR in β-cells of lean and obese mice.

Author information

1
Institute of Pharmacy (B.S., R.W., V.K., P.K.-D., G.D.), Department of Pharmacology, University of Tübingen and Medical Clinic IV (A.P.), D-72076 Tübingen, Germany; and Institute of Pharmaceutical and Medical Chemistry (M.D.), Department of Pharmacology, D-48149 Münster, Germany.

Abstract

We have recently shown that the bile acid (BA) taurochenodeoxycholate (TCDC) acutely stimulates insulin secretion via activation of the farnesoid X receptor (FXR). Aims of the current investigation were to discriminate between nongenomic (≤1 h) and genomic effects (24-48 h) of BAs on β-cells and to evaluate whether FXR can modulate the adverse effects of a high-fat diet (HFD). TCDC (500 nM) as well as glycine-conjugated and unconjugated CDC (chenodeoxycholate) increased insulin secretion in acute incubations but did not evoke additional effects after 1-2 days of preincubation. The BAs did not stimulate β-cells of FXR-knockout (KO) mice and activation of the G protein-coupled BA receptor TGR5 was ineffective, suggesting that FXR is the sole BA receptor in β-cells activated by TCDC and its analogues. As opposed to lean mice, obese FXR-KO mice did not show HFD-induced glucose intolerance and increased fasting glucose. The beneficial impact of FXR-KO on glucose metabolism cannot be explained by an adaptive compensation of insulin secretion or β-cell mass. Interestingly, in contrast to its effect on islets from lean mice, the FXR agonist GW4064 was ineffective in stimulating insulin secretion of islets from wild type mice fed a HFD or isolated islets kept in a glucolipotoxic medium. Additional feeding of CDC restored the effect of GW4064. CDC prevented HFD-induced impairment of glucose tolerance and in vitro effects of glucolipotoxicity. The data show that the FXR is the most important BA receptor in β-cells and that FXR signaling in β-cells is impaired by overnutrition, which alters activatability of the FXR.

PMID:
25599407
DOI:
10.1210/en.2014-1751
[Indexed for MEDLINE]

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