Abstract P166: Genetic Ablation of the Bile Acid Receptor- Takeda G-protein Coupled Receptor 5 (TGR5) Promotes Weight Gain but Lowers Hypertension

Abstract

Introduction: TGR5 belongs to G-protein coupled receptor family, that mediates bile acid signaling. Activation of TGR5 by bile acids triggers intestinal glucagon-like peptide-1 secretion, whereby pharmacological activation of TGR5 constitutes a promising incretin-based strategy for the treatment of metabolic disorders. Hypertension is one of the hallmark features of metabolic disorders. We previously reported that hypertension is associated with lower conjugated bile acids, which are ligands for TGR5. Therefore, we hypothesized that lack of activation of TGR5-mediated bile acid signaling promotes not only body weight gain, but also hypertension. Methods: CRISPR/Cas9 technology was used to generate Tgr5 -/- rats from hypertensive Dahl Salt-sensitive (S) rats. Twenty-four-hour blood pressure (BP) readings of 8-weeks-old control female Tgr5 +/+ S rats and age-matched female Tgr5 -/- S rats (n=7/group) were monitored by radiotelemetry for 4 weeks. Body weight, food intake, and water intake were recorded every week. At the end of the study, vascular function was examined using wire myography of dorsal and mesenteric resistance arteries, cardiac function was assessed by echocardiography, and microbiota profiling was conducted via fecal 16S rRNA gene sequencing using Miseq. Results: In support of our hypothesis, despite no difference in food and water intake, at 4 weeks, the body weights of Tgr5 -/- S rats were significantly higher compared to Tgr5 +/+ S rats (236.3gm vs. 225.4gm; p<0.01). Surprisingly, in contrast to our hypothesis, at 4 weeks, Tgr5 -/- S rats had significantly lower systolic BP (151.8mmHg vs. 156.9mmHg, p<0.0001), diastolic BP (107.9mmHg vs. 115.5mmHg, p<0.0001), and mean arterial BP (128.8mmHg vs. 134.9mmHg, p<0.0001) compared to Tgr5 +/+ S rats. However, no significant differences were observed either in vascular reactivity or cardiac function between the groups. Interestingly, fecal microbiota analysis revealed that Tgr5 -/- S rats presented with significant remodeling of gut microbiota with lower α-diversity (observed features; p=0.05), b-diversity (Bray-Curtis; p<0.05, Jaccard; p<0.01), and higher relative abundance of the BP-lowering genera Akkermansia . Conclusion: Our study revealed that deletion of TGR5 resulted in weight gain but lowered BP. It implies that activation of TGR5 may be a risk factor for raising BP. The mechanism by which TGR5 regulates BP seem independent of changes in vascular or cardiac function but is likely mediated by gut microbiota.