Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway

Abstract

ObjectiveGlucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown.MethodsWe investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r−/− and Tgr5−/− mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo.ResultsAcute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5−/− mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r−/− but not in Tgr5−/− mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner.ConclusionsOur data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease.

Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice

“…Although the actions of GLP-2 are predominantly localized to the gut (7), the extraintestinal expression of the GLP-2R raises important questions surrounding the safety of therapy with GLP-2R agonists, and potential actions of teduglutide beyond the gastrointestinal tract. For example, we recently detected robust expression of the GLP-2R in gallbladder and demonstrated that administration of teduglutide markedly inhibits gallbladder emptying in mice (8). These findings, subsequently extended to human studies, are consistent with reports of increased numbers of gallbladder-related adverse events associated with teduglutide therapy (9).…”

“…Sections were obtained from the proximal jejunum for RNA and protein analyses. Gallbladder volume measurement was performed as described previously (8). Briefly, the gallbladder was ligated to prevent emptying and resected prior to liver manipulation.…”

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…In contrast, upon reaching the ileum (lower small bowel), BA stimulation of glucagon-like peptide-2 (GLP-2) release from intestinal L-cells stimulates gallbladder refilling and may influence satiety. 30,31 As such, BAs are emerging as a potential mechanism of improving metabolic homeostasis.…”

Glucagon‐like peptide‐2 mobilizes lipids from the intestine by a systemic nitric oxide‐independent mechanism

“…* P < 0.05 vs. placebo + L-NMMA, ** P < 0.01 vs. placebo + L-NMMA that a meal challenge with high sucrose and high fat decreased wholebody NO production and NO-mediated vascular response, strongly related to plasma TG levels 30. Further, it is noted that at least certain physiological roles of GLP-2 are not regulated by NO, such as GLP-2 promotion of gallbladder refilling 31. Lastly, use of Ted, a dipeptidyl peptidase-4 resistant analogue of GLP-2 in this study is expected to cause sustained pharmacological activation of GLP-2 receptors, which may limit extrapolation of the results to physiological effects of endogenous GLP-2.…”