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 inflammation 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
- DIABETES MELLITUS
- GASTROINTESTINAL HORMONES
- COLONIC MICROFLORA
Statistics from Altmetric.com
Correction notice This article has been corrected since it published Online First. Figure 4 has been corrected.
Contributors AKM acquired and interpreted data and wrote the paper. DG, ZMH and JC acquired and interpreted data and revised the manuscript. AB, FGH and REL contributed to study design, data interpretation and revised the manuscript. MLC contributed to study design, acquired and interpreted data and revised the manuscript. BPC supervised the study, contributed to study design, data interpretation and finalised the manuscript.
Funding This research was supported by DK076169, funding from Eli Lilly, start-up support from Cornell University, the President's Council of Cornell Women and R01DK095960. BPC's laboratory also received funding during the project period from the Cornell Comparative Cancer Biology Training Program, the US Highbush Blueberry Council and U24DK092993. The FGH lab is supported by R01DK090492 and R01DK095359.
Competing interests BPC's laboratory receives funding from Eli Lilly and MLC is employed by Eli Lilly.
Ethica approval The experimental protocols were approved by the UC Davis and Cornell University Institutional Animal Care and Use Committees.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Gut microbiome data will be made publicly available through Qiime.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.