Glucagon‐like peptide‐2 stimulates the proliferation of cultured rat astrocytes

Velázquez, Esther; Ruiz-Albusac, Juan Miguel; Blázquez, Enrique

doi:10.1046/j.1432-1033.2003.03677.x

Cited by 41 publications

(38 citation statements)

References 56 publications

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“…Recent supportive data demonstrated that intestinal mucosal cells isolated from rat intestine express mRNA for the GLP-2 receptor and that these epithelial cells respond to GLP-2 stimulation via a cAMP-dependent pathway resulting in increased thymidine incorporation (55). Others (2,54) report that in murine species, the GLP-2 receptor is not located on the enterocyte but is localized to the neuronal elements of the enteric nervous system. In one of these studies, the administration of GLP-2 to mice stimulated a rapid increase in c-Fos expression, a marker of neuronal activation, in the myenteric plexus followed shortly by an increase in crypt cell c-Fos expression.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Martin¹,

Wallace²,

Sigalet³

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

135

121

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Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 μg·kg−1·h−1 GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals ( P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression ( P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

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Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Martin¹,

Wallace²,

Sigalet³

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

135

121

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“…There are scattered reports that VIP-secretin-glucagon-like peptides can influence the proliferation of neural progenitors. There has been a report that GLP2 influences the proliferation of astrocytes in culture (Velazquez et al, 2003). Similarly, pituitary adenylate cyclase activating peptide (PACAP), a member of the VIP-secretin-glucagon family of peptides, is known to suppress proliferation and antagonize the actions of Shh in the developing neural tube (Waschek et al, 2000;Nicot et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Glucagon-Expressing Neurons within the Retina Regulate the Proliferation of Neural Progenitors in the Circumferential Marginal Zone of the Avian Eye

Fischer

Omar²,

Walton³

et al. 2005

J. Neurosci.

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Glucagon-expressing retinal amacrine cells have been implicated in regulating postnatal ocular growth. Furthermore, experimentally accelerated rates of ocular growth increase the number of neurons added to the peripheral edge of the retina. Accordingly, we assayed whether glucagon-expressing neurons within the retina regulate the proliferation of progenitors in the circumferential marginal zone (CMZ) of the postnatal chicken eye. We found that glucagon-containing neurites are heavily clustered within the CMZ at the peripheral edge of the retina. Many of these neurites originate from a cell type that is distinct from other types of retinal neurons, which we termed large glucagon-expressing neurons (LGENs). The LGENs are immunoreactive for glucagon and glucagon-like peptide 1 (GLP1), have a unipolar morphology, produce an axon that projects into the CMZ, and are found only in ventral regions of the retina. In dorsal regions of the retina, a smaller version of the LGENs densely ramifies neurites in the CMZ. Intraocular injections of glucagon or GLP1 suppressed the proliferation of progenitors in the CMZ, whereas a glucagon-receptor antagonist promoted proliferation. In addition, we found that glucagon, GLP1, and glucagon antagonist influenced the number of progenitors in the CMZ. We conclude that the LGENs may convey visual information to the CMZ to control the addition of new cells to the edge of the retina. We propose that glucagon/GLP1 released from LGENs acts in opposition to insulin (or insulin-like growth factor) to regulate precisely the proliferation of retinal progenitors in the CMZ.

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“…The primary stimulus throughout the experiments was the addition of exogenous GLP-2 to the medium. GLP-2 (1-33 human; American Peptide, Sunnyvale, CA) was dissolved in sterile water and diluted to a final concentration in medium of 10 Ϫ8 M [optimal concentration for proliferation (15,38)]. On days 10 and 11, in the 0.1% FBS medium, cells were treated with GLP-2 10 Ϫ8 M or control medium for 1-28 days.…”

Section: Methodsmentioning

confidence: 99%

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

Heuvel¹,

Wallace²,

Sharkey

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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de Heuvel E, Wallace L, Sharkey KA, Sigalet DL. Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-␥ signaling. Am J Physiol Endocrinol Metab 303: E994 -E1005, 2012. First published August 14, 2012; doi:10.1152/ajpendo.00291.2012.-Glucagon-like peptide 2 (GLP-2) is an enteroendocrine hormone trophic for intestinal mucosa; it has been shown to increase enteric neuronal expression of vasoactive intestinal polypeptide (VIP) in vivo. We hypothesized that GLP-2 would regulate VIP expression in enteric neurons via a phosphatidylinositol-3 kinase-␥ (PI3K␥) pathway. The mechanism of action of GLP-2 was investigated using primary cultures derived from the submucosal plexus (SMP) of the rat and mouse colon. GLP-2 (10 Ϫ8 M) stimulation for 24 h increased the proportion of enteric neurons expressing VIP (GLP-2: 40 Ϯ 6% vs. control: 22 Ϯ 5%). GLP-2 receptor expression was identified by immunohistochemistry on neurons (HuC/Dϩ) and glial cells (GFAPϩ) but not on smooth muscle or fibroblasts in culture. Over 1-4 h, GLP-2 stimulation of SMP increased phosphorylated Akt/Akt ratios 6.1-fold, phosphorylated ERK/ERK 2.5-fold, and p70S6K 2.2-fold but did not affect intracellular cAMP. PI3K␥ gene deletion or pharmacological blockade of PI3K␥, mammalian target of rapamycin (mTOR), and MEK/ ERK pathways blocked the increase in VIP expression by GLP-2. GLP-2 increased the expression of growth factors and their receptors in SMP cells in culture [IGF-1r (3.2-fold increase), EGFr (5-fold), and ErbB-2-4r (6-to 7-fold)] and ligands [IGF-I (1.5-fold), amphiregulin (2.5-fold), epiregulin (3.2-fold), EGF (7.5-fold), heparin-bound EGF (2.0-fold), ␤-cellulin (50-fold increase), and neuregulins 2-4 (300-fold increase) (by qRT-PCR)]. We conclude that GLP-2 acts on enteric neurons and glial cells in culture via a PI3K␥/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, and expression of receptors and ligands for the IGF-I and ErbB pathways.differentiation; extracellular signal-regulated kinase; ErbB; epidermal growth factor receptor; insulin-like growth factor I; neuregulin THE ENTERIC NERVOUS SYSTEM (ENS) is an important regulator of intestinal function and is understood primarily in terms of the control and integration of gastrointestinal motility, blood flow, and secretion (10,11,20). The role of the ENS in regulating other aspects of intestinal function, such as nutrient absorption and response to inflammation and injury, is becoming increasingly appreciated (18,23,32). The ENS is able to alter neuronal morphology, function, and the pattern of neurotransmitter expression in response to inflammation (17,33). Enteric neurons also undergo changes in neurochemical phenotype in pathophysiological states such as inflammation (22,29). The mechanisms that may regulate the phenotype and pattern of transmitter expression in the ENS in vivo are not well understood (5). In recent work, we have shown that glucagon-like peptide 2 (GLP-2), known as a trophic ...

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Glucagon‐like peptide‐2 stimulates the proliferation of cultured rat astrocytes

Cited by 41 publications

References 56 publications

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Glucagon-Expressing Neurons within the Retina Regulate the Proliferation of Neural Progenitors in the Circumferential Marginal Zone of the Avian Eye

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

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