Roux-en-Y Gastric Bypass Surgery-Induced Weight Loss and Metabolic Improvements Are Similar in TGR5-Deficient and Wildtype Mice

Abstract

Background and PurposeRoux-en-Y gastric bypass surgery (RYGB) remains one of the most effective treatments for obesity and type 2 diabetes. Despite this, the mechanisms through which it acts are still not well understood. Bile acid signaling through the transmembrane G-protein-coupled receptor TGR5 has been shown to have significant effects on metabolism and has recently been reported to be necessary for the full effects of vertical sleeve gastrectomy (VSG), a bariatric surgery with similar effects to RYGB. The goal of the current study is therefore to investigate the role of bile acid signaling through TGR5 to see if it is necessary to obtain the full effects of RYGB.MethodsHigh-fat diet-induced obese TGR5−/− and wildtype mice (WT) were subjected to RYGB, sham surgery, or weight matching (WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance, insulin sensitivity, and liver weight were measured.ResultsAlthough the difference in fat mass 20 weeks after surgery between RYGB and sham-operated mice was slightly reduced in TGR5−/− mice when compared to wildtype mice, loss of body weight and fat mass from preoperative levels, reduction of food intake, increase of energy expenditure, and improvement in glycemic control were similar in the two genotypes. Furthermore, improvements in glycemic control were similar in non-surgical mice weight-matched to RYGB.ConclusionsWe conclude that bile acid signaling through TGR5 is not required for the beneficial effects of RYGB in the mouse and that RYGB and VSG may achieve their similar beneficial effects through different mechanisms.Electronic supplementary materialThe online version of this article (10.1007/s11695-018-3297-6) contains supplementary material, which is available to authorized users.

Effects of Obesity and Gastric Bypass Surgery on Nutrient Sensors, Endocrine Cells, and Mucosal Innervation of the Mouse Colon

“…This finding is likely to be a factor in increased GLP-1 secretion by TGR5 stimulation [ 29 ] after RYGB. However, we have recently demonstrated that TGR5 signaling is not required for any beneficial effects of RYGB in mice [ 30 ], suggesting that bile acid signaling through FXR may be more important [ 31 ].…”

TGR5 Signaling in Hepatic Metabolic Health

“…Zhai et al, suggest that ileal deoxycholic acid-TGR5-mTORC1 signaling contributes to increased GLP-1 production following RYGB in mice [78]. In contrast, Hao et al, reported similar improvements in glucose tolerance and insulin resistance, as assessed by insulin tolerance testing, in whole body Tgr5 +/+ and Tgr5 −/− mice following RYGB [77]. Overall, the differential effects of whole body TGR5 signaling on hepatic metabolic outcomes following bariatric surgery could stem from differences in the underlying mechanisms through which surgery types improve metabolic regulation.…”

“…Comparatively, Albaugh et al, detected a TGR5-independent improvement in glucose tolerance following bile diversion to the ileum (GB-IL) in mice, in which improvements in glucose tolerance following GB-IL was primarily due to a TGR5-independent effect of bile acids on improved hepatic insulin sensitivity [76]. Conversely, the results on the role of TGR5 in the metabolic benefits of Roux-en-Y gastric bypass (RYGB) have been mixed [77,78]. Zhai et al, suggest that ileal deoxycholic acid-TGR5-mTORC1 signaling contributes to increased GLP-1 production following RYGB in mice [78].…”

“…Following gallbladder bile diversion to the ileum (GB-IL), there is no TGR5-dependent improvement in insulin sensitivity [76]. Roux-en-Y gastric bypass (RYGB) has no TGR5-dependent effect on glucose tolerance [77].…”

Mikrobiom und metabolische/bariatrische Chirurgie

“…Trotzdem muss festgehalten werden, dass diese Arbeit nur Assoziationen und keine mechanistische Rolle der Gallensäuren in der vermehrten Aktivierung der L-Zellen beweist. Bisher verfügbare experimentelle Daten sind bislang kontrovers und nicht in jedem Modell konnte eine Abhängigkeit der L-Zellantwort von einem intakten TGR5 Rezeptor gezeigt werden [61].…”