TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice

Abstract

Objective Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. Design VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5−/− (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. Results VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic infiammation and islet morphology after VSG were attenuated in Tgr5−/− relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5−/− relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. Conclusions These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.

Bile acid signaling and bariatric surgery

“…Similarly, McGavigan et al 14 generated an independent TGR5 knockout mouse line and obtained results that were consistent with Ding’s observations that VSG improved fasting glycemia, glucose tolerance, and glucose-stimulated insulin secretion. VSG also produced favorable shifts in gut microbial populations in both genotypes.…”

“…That study, backed up by Dr. Ding’s study, suggests that TGR5 is a molecular target of bariatric surgery. 14 However, it remains unclear which VSG-generated signals activate TGR5 and the specific downstream effectors of postoperative TGR5 activation.…”

Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism

“…We have also shown that FXR is an important contributor to the weight loss and improved glucose metabolism after bariatric surgery in mice (Ryan et al, 2014). In contrast, experiments with Tgr5-deficient mice showed that TGR5 did not contribute to the reduced body weight, increased energy expenditure, or increased glucose-stimulated insulin secretion after vertical sleeve gastrectomy (VSG) (McGavigan et al, 2015). However, glucose tolerance, hepatic insulin signaling, and metabolically favorable changes in bile acid profiles after VSG were attenuated in the Tgr5-deficient mice, indicating that TGR5 has an impact on at least some of the beneficial effects after bariatric surgery.…”

Gut-Brain Cross-Talk in Metabolic Control

“…Whole-body deletion of FXR results in mice that gain less weight on a HFD but nevertheless have reduced responses to VSG for long-term weight loss, reductions in food intake, and improvements in glucose tolerance (Ryan et al, 2014). Mice with no TGR5 signaling have normal body weight loss following VSG, but have less improvements in glucose regulation (McGavigan et al, 2017). The point is that molecular targeting of bile acid signaling provides evidence that alterations in bile acids are an important physiological mechanism by which surgical intervention can alter energy balance and metabolism.…”