Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

Abstract

The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…The discrepancy could be attributed to different species; however, caution should be taken in ruling out a glucagonotrophic role of GLP2 in mice. In fact, recent researches have demonstrated that GLP2R is more widely expressed than it was estimated (Angelone et al 2012, El-Jamal et al 2014. Therefore, it is necessary to explore the presence and localization of GLP2R in the pancreatic islets using validated GLP2R antibody and the opportune positive and negative controls to yield to conclusive results.…”

“…It is well known that reduced adiposity could contribute to the preservation of insulin sensitivity because the adipose tissue has a considerable influence on systemic glucose homeostasis through secretion of adipocytokines (McArdle et al 2013). Interestingly, Glp2r mRNA expression has been detected in mouse mesenteric adipose tissue (El-Jamal et al 2014); however, its functional significance is still unknown. It is important to characterize whether GLP2 increases glucose incorporation in adipocytes when their response to insulin is impaired by obesity conditions.…”

“…Mouse liver expresses GLP2R (El-Jamal et al 2014); however, nothing is known about other species, including humans. Moreover, fatty liver is strongly associated with insulin resistance (Asrih & Jornayvaz 2013), and non-alcoholic hepatic steatosis has been reported in HFD-fed mice (de Meijer et al 2010, Fraulob et al 2010.…”

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

“…Since that time, numerous subtypes of endocrine cells within the intestinal mucosa and their peptide products have been characterized [2]. These enteric peptides have become the subject of intensive scientific investigation regarding regulation of their release [3][4][5], mechanisms of action [6][7][8], and diverse physiological effects, including those outside the digestive system such as bone [9], liver [10], lung [11], and the central nervous system [12][13][14]. This primarily was due to the discovery that enteric peptides, such as glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and peptide YY, play key roles in the regulation of appetite, energy metabolism [15][16][17], and gut function [18][19][20], making them targets for managing prevalent human diseases of obesity and diabetes.…”

GLP-2: What do we know? What are we going to discover?

“…The GLP-2R is expressed by myofibroblasts [26] and it was hypothesized that GLP-2 exerts its trophic actions indirectly through myofibroblasts as well. Indeed, GLP-2 signalling induces the release of several growth factors such us insulin-like growth factor-1 and keratinocyte growth factor, that are responsible for the proliferative effects of GLP-2.…”