GLP-2 receptor signaling controls circulating bile acid levels but not glucose homeostasis in Gcgr mice and is dispensable for the metabolic benefits ensuing after vertical sleeve gastrectomy

Abstract

ObjectiveTherapeutic interventions that improve glucose homeostasis such as attenuation of glucagon receptor (Gcgr) signaling and bariatric surgery share common metabolic features conserved in mice and humans. These include increased circulating levels of bile acids (BA) and the proglucagon-derived peptides (PGDPs), GLP-1 and GLP-2. Whether BA acting through TGR5 (Gpbar1) increases PGDP levels in these scenarios has not been examined. Furthermore, although the importance of GLP-1 action has been interrogated in Gcgr−/− mice and after bariatric surgery, whether GLP-2 contributes to the metabolic benefits of these interventions is not known.MethodsTo assess whether BA acting through Gpbar1 mediates improved glucose homeostasis in Gcgr−/− mice we generated and characterized Gcgr−/−:Gpbar1−/− mice. The contribution of GLP-2 receptor (GLP-2R) signaling to intestinal and metabolic adaptation arising following loss of the Gcgr was studied in Gcgr−/−:Glp2r−/− mice. The role of the GLP-2R in the metabolic improvements evident after bariatric surgery was studied in high fat-fed Glp2r−/− mice subjected to vertical sleeve gastrectomy (VSG).ResultsCirculating levels of BA were markedly elevated yet similar in Gcgr−/−:Gpbar1+/+ vs. Gcgr−/−:Gpbar1−/− mice. Loss of GLP-2R lowered levels of BA in Gcgr−/− mice. Gcgr−/−:Glp2r−/− mice also exhibited shifts in the proportion of circulating BA species. Loss of Gpbar1 did not impact body weight, intestinal mass, or glucose homeostasis in Gcgr−/− mice. In contrast, small bowel growth was attenuated in Gcgr−/−:Glp2r−/− mice. The improvement in glucose tolerance, elevated circulating levels of GLP-1, and glucose-stimulated insulin levels were not different in Gcgr−/−:Glp2r+/+ vs. Gcgr−/−:Glp2r−/− mice. Similarly, loss of the GLP-2R did not attenuate the extent of weight loss and improvement in glucose control after VSG.ConclusionsThese findings reveal that GLP-2R controls BA levels and relative proportions of BA species in Gcgr−/− mice. Nevertheless, the GLP-2R is not essential for i) control of body weight or glucose homeostasis in Gcgr−/− mice or ii) metabolic improvements arising after VSG in high fat-fed mice. Furthermore, despite elevations of circulating levels of BA, Gpbar1 does not mediate elevated levels of PGDPs or major metabolic phenotypes in Gcgr−/− mice. Collectively these findings refine our understanding of the relationship between Gpbar1, elevated levels of BA, PGDPs, and the GLP-2R in amelioration of metabolic derangements arising following loss of Gcgr signaling or after vertical sleeve gastrectomy.

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche

“…(Gcg -/-) mice, Villin 1-cre mice, and GLP-2 receptor (Glp2r -/-) knockout mice were as previously reported (51,52). Mice were housed in a 12-hour light/dark cycle in the Unit for Laboratory Animal Medicine at the University of Michigan, with free access to water.…”

Mechanisms for the metabolic success of bariatric surgery

“…Preclinical studies in rats demonstrate that the increase in GLP‐2 occurs in parallel with intestinal hypertrophy after RYGB . However, mice null for the GLP‐2 receptor lose weight and improve glucose tolerance similar to wild‐type animals in response to VSG . Given its link to glucose sensing and absorption in the gut, the increase in GLP‐2 with RYGB could also blunt some of the macronutrient malabsorption that would be expected to increase with intestinal rearrangement, an effect minimised with VSG.…”

“…Thus, more research is needed from independent groups utilising sensitive and specific assays to determine whether glucagon is increased with surgery or not. Regardless, if glucagon does increase, it may not be critical in the success of surgery because genetic deficiency of both the glucagon receptor and the GLP‐2 receptor does not blunt the metabolic benefits of VSG …”

“…46 However, mice null for the GLP-2 receptor lose weight and improve glucose tolerance similar to wild-type animals in response to VSG. 47 Given its link to glucose sensing and absorption in the gut, 48 the increase in GLP-2 with RYGB could also blunt some of the macronutrient malabsorption that would be expected to increase with intestinal rearrangement, an effect minimised with VSG. Thus, these apparent differences could reflect the varied impact of the specific surgeries or it could simply be that the increase in GLP-2 and consequent increase in hypertrophy that occurs with RYGB is a marker but not a mechanism of the success of surgery.…”

“…Regardless, if glucagon does increase, it may not be critical in the success of surgery because genetic deficiency of both the glucagon receptor and the GLP-2 receptor does not blunt the metabolic benefits of VSG. 47 Oral glucose drives a much greater insulin response compared to when the same glucose load is administered i.v. 55 This incretin effect is attributed to GLP-1 and GIP.…”