Mechanism of Action of Glucagon-Like Peptide-2 to Increase IGF-I mRNA in Intestinal Subepithelial Fibroblasts

Department of Physiology,University of Toronto, Toronto, Ontario, Canada.
Endocrinology (Impact Factor: 4.5). 02/2011; 152(2):436-46. DOI: 10.1210/en.2010-0822
Source: PubMed


IGF-I, a known secretory product of intestinal subepithelial myofibroblasts (ISEMFs), is essential for the intestinotropic effects of glucagon-like peptide-2 (GLP-2). Furthermore, GLP-2 increases IGF-I mRNA transcript levels in vitro in heterogeneous fetal rat intestinal cultures, as well as in vivo in the rodent small intestine. To determine the mechanism underlying the stimulatory effect of GLP-2 on intestinal IGF-I mRNA, murine ISEMF cells were placed into primary culture. Immunocytochemistry showed that the ISEMF cells appropriately expressed α-smooth muscle actin and vimentin but not desmin. The cells also expressed GLP-2 receptor and IGF-I mRNA transcripts. Treatment of ISEMF cells with (Gly2)GLP-2 induced IGF-I mRNA transcripts by up to 5-fold of basal levels after treatment with 10(-8) m GLP-2 for 2 h (P < 0.05) but did not increase transcript levels for other intestinal growth factors, such as ErbB family members. Immunoblot revealed a 1.6-fold increase in phospho (p)-Akt/total-(t)Akt with 10(-8) m GLP-2 treatment (P < 0.05) but no changes in cAMP, cAMP-dependent β-galactosidase expression, pcAMP response element-binding protein/tcAMP response element-binding protein, pErk1/2/tErk1/2, or intracellular calcium. Furthermore, pretreatment of ISEMF cells with the phosphatidylinositol 3 kinase (PI3K) inhibitors, LY294002 and wortmannin, abrogated the IGF-I mRNA response to GLP-2, as did overexpression of kinase-dead Akt. The role of PI3K/Akt in GLP-2-induced IGF-I mRNA levels in the murine jejunum was also confirmed in vivo. These findings implicate the PI3K/Akt pathway in the stimulatory effects of GLP-2 to enhance intestinal IGF-I mRNA transcript levels and provide further evidence in support of a role for IGF-I produced by the ISEMF cells in the intestinotropic effects of GLP-2.

31 Reads
  • Source
    • "However, GLP-2R has the ability to couple to different G protein subunits and to activate multiple signalling pathways [18]. Studies using cells that naturally express the receptor suggest that phosphatidylinositol 3-kinase- γ[PI3Kγ] and subsequent Akt phosphorylation are the intracellular pathways activated by GLP-2 [19] [20]. The enteric nervous system seems to be a key component in the GLP-2 action, and this was initially evident for one of the GLP-2's main activities, namely its ability to enhance intestinal epithelial growth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucagon-like peptide 2 [GLP-2] is a 33-amino acid peptide released from the mucosal enterendocrine L-cells of the intestine. The actions of GLP-2 are transduced by the GLP-2 receptor [GLP-2R], which is localized in the neurons of the enteric nervous system but not in the intestinal epithelium, indicating an indirect mechanism of action. GLP-2 is well known for its trophic role within the intestine and interest in GLP-2 is now reviving based on the approval of the GLP-2R agonist for treatment of short bowel syndrome [SBS]. Recently it also seems to be involved in glucose homeostasis. The aim of this review is to outline the importance of neuroendocrine peptides, specifically of GLP-2 in the enteric modulation of the gastrointestinal function and to focus on new works in order to present an innovative picture of the GLP-2.
    Regulatory Peptides 09/2014; 194-195. DOI:10.1016/j.regpep.2014.09.002 · 1.83 Impact Factor
  • Source
    • "ed for GLP - 2 to have its major trophic effects on the small intestine . In those studies using an IGF - 1 − / − mouse , the stimulatory effects of GLP - 2 were abrogated ( Dubé et al . , 2006 ) . In further work , they have also shown that the IGF - 1 re - sponse appears to be mediated by GLP - 2 stimulation of the peri - cryptal myofibroblast ( Leen et al . , 2011 ) . The myofibroblasts are a localized cell group , physically cra - dling the crypt zone , and so are uniquely positioned to provide significant regulatory input into both the pro - liferation and differentiation of the crypt cells as they"
    [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of nutrient absorptive capacity is a critical factor in the normal growth and development of infants of all species. In human infants this is a common problem after surgical resection; the process of adaptation or upregulation of nutrient transport capacity is the physiologic process, which allows patients to transition to enteral feeding. The specific mechanisms that control this are still relatively poorly understood but are likely relevant for most mammals with an ontogeny of intestinal function related to the weaning process. Many actions of the entero-endocrine hormone glucagon-like peptide (GLP)-2 indicate that it may be a key factor in regulating physiologic intestinal development, nutrient absorptive capacity, and the process of adaptative upregulation of nutrient absorption after resection. This article will review the biology of GLP-2, which is preserved across a broad range of species. This will include the production of GLP-2 in the L cell, the regulation of GLP-2 release, and the mechanism of action. The GLP-2 receptor is specifically located on enteric neurons and pericryptal myofibroblast; thus, effects on the intestinal mucosa involve a second messenger. We will review the functioning of this system in the developing human infant and the role of GLP-2 in the regulation of adaptation, with the general implications for nutrient absorption in animals and humans.
    Journal of Animal Science 11/2011; 90(4):1224-32. DOI:10.2527/jas.2011-4704 · 2.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.
    AJP Gastrointestinal and Liver Physiology 04/2011; 301(1):G1-8. DOI:10.1152/ajpgi.00039.2011 · 3.80 Impact Factor
Show more