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. 2012:2:430.
doi: 10.1038/srep00430. Epub 2012 May 30.

TGR5 potentiates GLP-1 secretion in response to anionic exchange resins

Taoufiq Harach  1 , Thijs W H Pols, Mitsunori Nomura, Adriano Maida, Mitsuhiro Watanabe, Johan Auwerx, Kristina Schoonjans
Affiliations

TGR5 potentiates GLP-1 secretion in response to anionic exchange resins

Taoufiq Harach et al. Sci Rep. 2012.

Abstract

Anionic exchange resins are bona fide cholesterol-lowering agents with glycemia lowering actions in diabetic patients. Potentiation of intestinal GLP-1 secretion has been proposed to contribute to the glycemia lowering effect of these non-systemic drugs. Here, we show that resin exposure enhances GLP-1 secretion and improves glycemic control in diet-induced animal models of "diabesity", effects which are critically dependent on TGR5, a G protein-coupled receptor that is activated by bile acids. We identified the colon as a major source of GLP-1 secretion after resin treatment. Furthermore, we demonstrate that the boost in GLP-1 release by resins is due to both enhanced TGR5-dependent production of the precursor transcript of GLP-1 as well as to the local enrichment of TGR5 agonists in the colon. Thus, TGR5 represents an essential component in the pathway mediating the enhanced GLP-1 release in response to anionic exchange resins.

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Figures

Figure 1
Figure 1. Potentiation of GLP-1 secretion by AERs is TGR5-dependent.
(a–f) Analysis of plasma from diet-induced obese TGR5+/+ and TGR5−/− mice after two weeks of treatment with Colestilan (COL; n = 7 per group). GLP-1 (a–b), insulin (c–d), and glucose (e–f) levels at indicated time points after test meal. Data represent mean ± SE. *Statistically significant, p<0.05, **p<0.01, ***p<0.001.
Figure 2
Figure 2. Enhanced proglucagon transcription in enteroendocrine cells in response to INT-777 requires TGR5.
(a–b) TGR5 (a) and proglucagon (b) mRNA levels in the different intestinal sections of diet-induced obese TGR5+/+ and TGR5−/− mice after two weeks of treatment with Colestilan (COL; n = 7 per group). (c–d) Proglucagon mRNA levels in STC-1 (c) and GLUTag (d) mouse enteroendocrine cells transfected with shControl or shTGR5 vectors in the presence of 30 µM INT-777 (black bars) or vehicle (white bars; n = 3 per group). (e–f) INT-777 induces proglucagon promoter activity via TGR5 in enteroendocrine cells. STC-1 (e) and GLUTag (f) mouse enteroendocrine cells were transfected with shControl or shTGR5 constructs in combination with the proglucagon luciferase reporter. Cells were then incubated with vehicle (white bars) or 30 µΜ INT-777 (black bars; n = 3 per group) for 3 hours and assayed for luciferase activity. Data represent mean ± SE. *Statistically significant, p<0.05.
Figure 3
Figure 3. TGR5-dependent GLP-1 secretion is induced by acute exposure of AERs.
(a–b) Plasma GLP-1 levels at indicated time points after test meal from high fat diet-induced obese TGR5+/+ mice (a) and TGR5−/− littermates (b) after three hours of treatment with Colestilan (COL; n = 7 per group). Data represent mean ± SE. *Statistically significant as compared to control group, p<0.05.
Figure 4
Figure 4. TGR5 signaling is induced by colon content of mice treated with AERs.
(a) GLP-1 release from explants of different intestinal segments of TGR5+/+ mice. Duodenum (duo). (b) GLP-1 release from colon explants of TGR5+/+ and TGR5−/− mice (n = 6 per group) in response to 1 hour treatment with 30 µM INT-777 or 15 µM LCA/DCA. Mice were fed a high fat diet for 10 weeks prior to the collection of explants. (c) GLP-1 secretion from colon explants of TGR5+/+ and TGR5−/− mice fed a high fat diet for 2 weeks and subsequently treated with Colestilan for two additional weeks (n = 6 per group). (d) Luciferase activity in CHO cells transiently transfected with TGR5 expression vector and a cAMP response element (CRE)-driven luciferase reporter vector. Cells were treated with DMSO vehicle (white bars), 10 µM litocholic acid (LCA; black bars), colon content collected from untreated wildtype mice (light gray bars), or colon content collected from Colestilan-treated wildtype mice (dark gray bars; n = 5 per group). The mice cohorts used for the collection of colon content were fed a high fat diet for 10 weeks prior treatment with Colestilan for 2 weeks. (e) GLP-1 release from colon explants of TGR5+/+ and TGR5−/− mice (n = 6 per group) in response to 1 hour exposure of colon content derived from untreated wildtype mice (light gray bars), or colon content collected from Colestilan-treated wildtype mice (n = 5 per group). Data represent mean ± SE. *Statistically significant, p<0.05; **: p<0.01.
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