Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

Abstract

Abbreviations: APO, apolipoprotein; CD36, cluster-of-differentiation 36; DFTT, duodenal fat tolerance test; FATP-4, fatty acid transfer protein-4; h(GLY 2 ) GLP-2, human glycine 2 -glucagon-like peptide-2; IE-IGF-1R, intestinal epithelial-insulin-like growth factor-1 receptor; KO, knockout; MTP, microsomal triglyceride transfer protein; OFTT, oral fat tolerance test; WD, Western diet. AbstractThe intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY 2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C 14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration.IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C 14 -fat accumulation, and elevated plasma triglyceride and C 14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

Perspective: Prospects for Nutraceutical Support of Intestinal Barrier Function

“…GLP-2 does not act directly on enterocytes, but rather acts on intestinal subepithelial fibroblasts, which respond by secreting insulin-like growth factor I (IGF-I) (10). The latter acts on enterocytes to stimulate the PI3K/Akt/mTORC1 pathway, thereby promoting enterocyte proliferation, inhibiting enterocyte apoptosis, and supporting the formation and maintenance of tight junctions (7,(11)(12)(13)(14). GLP-2 fails to exert these effects on enterocytes that lack IGF-I receptors, so IGF-I is an essential mediator of the trophic impact of GLP-2 on intestinal epithelium (12).…”

“…The latter acts on enterocytes to stimulate the PI3K/Akt/mTORC1 pathway, thereby promoting enterocyte proliferation, inhibiting enterocyte apoptosis, and supporting the formation and maintenance of tight junctions (7,(11)(12)(13)(14). GLP-2 fails to exert these effects on enterocytes that lack IGF-I receptors, so IGF-I is an essential mediator of the trophic impact of GLP-2 on intestinal epithelium (12). The PI3K/Akt/mTORC1signaling pathway triggered by IGF-I activity on enterocytes can induce expression at the mRNA and protein level of a range of proteins required for tight junction formation, including occludin, claudins, and ZO-1 (15)(16)(17)(18)(19)(20).…”

The Aging Bowel Dysfunction and Elderly Vulnerability towards COVID-19 Infection

“…This peptide acts locally on subepithelial fibroblasts to stimulate their secretion of insulin-like receptor I (IGF-I), which in turn acts to boost PI3K/Akt/mTORC1 signaling in enterocytes. This exerts an anabolic effect, promoting proliferation and suppressing apoptosis of enterocytes, but also supporting the formation and maintenance of tight junctions [85][86][87]. Notably, the PI3K/Akt/mTORC1 signaling pathway triggered by IGF-I activity on enterocytes has been shown to upregulate mRNA and protein levels of a range of proteins required for tight junction formation and function, including occludin, claudins, and ZO-1 [88].…”

Dapiglutide, a novel dual GLP‐1 and GLP‐2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel

“…GLP‐1 primarily exerts incretin activity, delays gastric emptying, prolongs intestinal transit, and promotes satiety in the central nervous system 9 . GLP‐2 primarily stimulates villus growth and enhances transepithelial absorption 10–12 . In the setting of IF, until now, only GLP‐2 signaling has been targeted pharmacologically to enhance intestinal absorption and clinical adaptation.…”