Role of FXR in β-Cells of Lean and Obese Mice
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...
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Veröffentlicht in: | Endocrinology (Philadelphia) 2015-04, Vol.156 (4), p.1263-1271 |
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Sprache: | eng |
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Zusammenfassung: | 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 (500nM) 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. |
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ISSN: | 0013-7227 1945-7170 |
DOI: | 10.1210/en.2014-1751 |