Synergistic Effect of Glucagon-Like Peptide 2 (GLP-2) and of Key Growth Factors on the Proliferation of Cultured Rat Astrocytes. Evidence for Reciprocal Upregulation of the mRNAs for GLP-2 and IGF-I Receptors

Abstract

The aim of this work was to determine whether the stimulating effect of glucagon-like peptide (GLP)-2 on astrocyte proliferation could be reinforced by proliferating substances, including growth factors such as EGF, platelet-derived growth factor, insulin-like growth factor type I (IGF-I) or a hormone such as insulin. Both DNA synthesis and astrocyte density, as well as the expression of c-Fos, Ki-67, proliferating cell nuclear antigen and glial fibrillary acidic proteins, were found to be higher in the presence of GLP-2 than in its absence. In an attempt to get a better understanding of this process, intracellular cyclic adenosine monophosphate (cAMP) production, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and the expression of GLP-2R and IGF-I receptor (IGF-IR) mRNAs were studied in response to growth factors. Our results indicate that, in the presence of different growth factors, GLP-2 does not increase cAMP production but raises ERK 1/2 phosphorylation. In addition, GLP-2R mRNA expression was increased by IGF-I, whilst mRNA expression of IGF-IR was higher in cells incubated with GLP-2 than in control cells. These results suggest for the first time that GLP-2 and several growth factors show synergistic effects on the proliferation of rat astrocytes, a process in which an enhanced expression of GLP-2R and IGF-IR may be involved, providing additional insights into the physiological role of this novel neuropeptide, specially during astroglial regeneration.

Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

“…Focusing on the intracellular signaling pathways involved, the present studies confirm the signaling events suggested in previous work done using intestinal myofibroblasts, CNSderived astrocytes, and hippocampal cell models (15,31,37). In these systems, increased cAMP was not a constitutive element in the GLP-2 response (15, 31, 37), which was confirmed in the present study.…”

“…Similar demonstrations of GLP-2 activation and regulation of neuronal phenotype have been shown in vivo in the ENS and in cultures of embryonic hippocampal neurons (31,33). However, a similar GLP-2-linked Akt-activated pathway was demonstrated in cultured astrocytes from the CNS (37,38). In the present study, enteric glial cells were also shown to specifically express the GLP-2 receptor, whereas the other main constituents of the cell preparation, smooth muscle cells and the fibroblasts, did not.…”

GLP‐2 receptor expression in excitatory and inhibitory enteric neurons and its role in mouse duodenum contractility

“…The presence of GLP‐2R has been reported in the central nervous system and in the gastrointestinal tract 9,11,13–16 . In particular, high levels of GLP‐2R mRNA have been found in the jejunum, followed by duodenum, ileum, colon, and stomach 9,17 and, by immunocytochemical techniques, GLP‐2R expression was detected in subsets of human and mouse endocrine cells of the stomach, and small, 16 and large intestine 15 .…”

“…11,12 The presence of GLP-2R has been reported in the central nervous system and in the gastrointestinal tract. 9,11,[13][14][15][16] In particular, high levels of GLP-2R mRNA have been found in the jejunum, followed by duodenum, ileum, colon, and stomach 9,17 and, by immunocytochemical techniques, GLP-2R expression was detected in subsets of human and mouse endocrine cells of the stomach, and small, 16 and large intestine. 15 Guan and co-workers 18 detected GLP-2R-immunoreactivity (IR) in the enteroendocrine cells and myenteric neurons of porcine jejunum where it co-localized with serotonin in the former and with endothelial nitric oxide synthase (eNOS) and vasoactive intestinal polypeptide (VIP) in the latter.…”

c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines

“…Another report showed that administration of low-dose GLP-1 combined with glucagon inhibited food intake-induced c-Fos expression in the area postrema and amygdala [14]. Moreover, the effect of glucagon-like peptide-2 (GLP-2) on c-Fos has been studied in primary rat astroglial cell cultures [15], and it has been demonstrated that GLP-2 has a role in hypertension regulation evaluated by c-Fos induction [16,17]. Ghrelin (GHR) and obestatin (OB) can also modulate c-Fos expression, GHR at neuronal level and so alter feeding patterns in rats and OB) in mouse embryonic fibroblast and adipose-like cells.…”