The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

Abstract

ObjectiveThe prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice.MethodsWe used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (Glp1r), GLP-2 receptor (Glp2r), and preproglucagon (Gcg) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG).ResultsComparison of Glp1r, Glp2r, and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r−/− mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology.ConclusionThe present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent.

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

“…GLP‐2 receptors are not expressed on enterocytes where chylomicron synthesis and assembly occur. Instead, they are mostly identified on enteroendocrine neurons and subepithelial myofibroblasts, many of which are located in the subepithelial regions of the intestine, including the lamina propria. In the current study, GLP‐2 increased TG and apoB48 concentrations in chylomicrons in a similar fashion, suggesting mobilization of whole chylomicron particles, rather than mobilizing intracellular TG to assemble larger particles.…”

“…post‐chylomicron assembly and secretion from the enterocyte) . Although GLP‐2 receptors are expressed abundantly in the gastrointestinal tract, they are identified on enteroendocrine neurons and subepithelial myofibroblasts, but not on enterocytes …”

“…post-chylomicron assembly and secretion from the enterocyte). 5 Although GLP-2 receptors are expressed abundantly in the gastrointestinal tract, they are identified on enteroendocrine neurons and subepithelial myofibroblasts, [12][13][14][15] but not on enterocytes. 16,17 Recent evidence in animal models suggests that nitric oxide (NO) is a mediator of some of GLP-2's actions.…”

Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

“…In addition, GLP-1R agonists promoted intestinal growth (Kissow et al, 2012;Simonsen et al, 2007) through fibroblast growth factor 7 (Koehler et al, 2015), and exogenous GLP-1 protects the gut against oxidative damage (Deniz et al, 2015). Whereas the contribution of endogenously secreted GLP-1 to gut growth appears to be modest (Wismann et al, 2017), endogenous GLP-1 contributes to gut recovery in the pathophysiological context of chemotherapy (Kissow et al, 2013). Thus, the 4.8-fold increase in GLP-1 secretion observed here could also modulate gut homeostasis through local actions to restore gut integrity.…”

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

“…Moreover, the rapid suppression of postprandial chylomicron and triglyceride levels is independent of gastric emptying (48) and is sustained with prolonged GLP-1R agonism in humans (49). Nevertheless, within the gastrointestinal tract of rodents and humans, the GLP-1R is predominantly localized to enteric neurons and lymphocytes and not detected within enterocytes (50). Hence, the suppression of enterocyte chylomicron secretion observed with GLP-1R agonists is likely indirect, perhaps mediated by neural signals.…”