Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport

Abstract

ObjectiveGlucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice.MethodsAbsorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r+/+ and Glp2r−/− mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2r+/+ and Glp2r−/− mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively.ResultsAcute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo. GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo. Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r−/− mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage, was significantly attenuated in Glp2r−/− mice.ConclusionsThese findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption.

T1R2 receptor-mediated glucose sensing in the upper intestine potentiates glucose absorption through activation of local regulatory pathways

“…Consistent with this hypothesis, elimination of the T1R2 receptor-mediated glucose sensing mechanism tampers both glucose absorption and disposal proportionally, thus maintaining postprandial glucose homeostasis in T1R2-KO mice. Notably, GLP-2 also regulates the transport of luminal amino acids [43] and fatty acids [44] , suggesting, along with our findings, an instrumental role of GLP-2 in regulating acute macronutrient absorption which, as shown here, is independent from changes in the intestinal absorptive area or morphology [35] .…”

Comparison of the Levels of C-Reactive Protein, GLP-1 and GLP-2 Among Individuals With Diabetes, Morbid Obesity and Healthy Controls: An Exploratory Study

“…Conversely, significantly lower levels of GLP-2 were observed in the non-diabetic with morbid obesity and diabetic with mild obesity groups than in the healthy controls. Since the stimuli for GLP-1 and GLP-2 are the same, and they are regularly secreted in equimolar proportions by the L-cells (1,(4)(5)(6)(7)(8) , there seems to be a common feature in both groups with obesity that solely impairs the GLP-2 levels, without compromising the GLP-1 secretion. This feature may be related to a specific imbalance of the homones secretion kinetics, which may be an impairment in the proglucagon conversion to GLP-2 or a faster degradation.…”

“…It is secreted by means of proteolytic cleavage of proglucagon in response to the passage of nutrients through the distal small bowel, in a 1:1 ratio with glucagon-like peptide 1 (GLP-1) in a process mediated by enzymes proglucagon convertase 1/3 (1)(2)(3)(4)(5)(6)(7)(8) . Although the properties of GLP-2 have not been completely elucidated to date, it presents several known physiologic functions, of which the main are the trophic effect on the gut mucosa and the enhancement of nutrient absorption (5)(6)(7)(8)(9)(10)(11)(12)(13) . GLP-1 is mainly enrolled in glucose homeostasis, and its main effects are the increasing of pancreatic beta cell function and the improvement of insulin sensitivity (14,15) .…”

Intestinal enteroendocrine L cells in amino acid sensing and diseases

“…Amino acids regulate secretion of various hormones such as GLP-1, GLP-2 and PYY in L cells by activating specific signaling pathways that trigger (81)(82)(83). These hormones work independently or collaboratively with each other to regulate appetite and maintain energy homeostasis (35).…”