title: Role of FXR in β-cells of lean and obese mice.
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.
authors.affiliation: 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.
authors.forename: Björn
authors.initials: B
authors.lastname: Schittenhelm
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wagner
authors.forename: Verena
authors.initials: V
authors.lastname: Kähny
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.forename: Peter
authors.initials: P
authors.lastname: Krippeit-Drews
authors.forename: Martina
authors.initials: M
authors.lastname: Düfer
authors.forename: Gisela
authors.initials: G
authors.lastname: Drews
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D005947:Glucose; D007328:Insulin; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013655:Taurochenodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064