scholarly journals Intestinotrophic Glucagon-Like Peptide-2 (GLP-2) Activates Intestinal Gene Expression and Growth Factor-Dependent Pathways Independent of the Vasoactive Intestinal Peptide Gene in Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2623-2632 ◽  
Author(s):  
Bernardo Yusta ◽  
Dianne Holland ◽  
James A. Waschek ◽  
Daniel J. Drucker
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Small Bowel ◽  
Vasoactive Intestinal Peptide ◽  
Paneth Cell ◽  
Crypt Cell ◽  
Colonic Injury ◽  
Intestinal Phenotype ◽  
Crypt Cell Proliferation ◽  
Glucagon Like Peptide

The enteroendocrine and enteric nervous systems convey signals through an overlapping network of regulatory peptides that act either as circulating hormones or as localized neurotransmitters within the gastrointestinal tract. Because recent studies invoke an important role for vasoactive intestinal peptide (VIP) as a downstream mediator of glucagon-like peptide-2 (GLP-2) action in the gut, we examined the importance of the VIP-GLP-2 interaction through analysis of Vip−/− mice. Unexpectedly, we detected abnormal villous architecture, expansion of the crypt compartment, increased crypt cell proliferation, enhanced Igf1 and Kgf gene expression, and reduced expression of Paneth cell products in the Vip−/− small bowel. These abnormalities were not reproduced by antagonizing VIP action in wild-type mice, and VIP administration did not reverse the intestinal phenotype of Vip−/− mice. Exogenous administration of GLP-2 induced the expression of ErbB ligands and immediate-early genes to similar levels in Vip+/+vs. Vip−/− mice. Moreover, GLP-2 significantly increased crypt cell proliferation and small bowel growth to comparable levels in Vip+/+vs. Vip−/− mice. Unexpectedly, exogenous GLP-2 administration had no therapeutic effect in mice with dextran sulfate-induced colitis; the severity of colonic injury and weight loss was modestly reduced in female but not male Vip−/− mice. Taken together, these findings extend our understanding of the complex intestinal phenotype arising from loss of the Vip gene. Furthermore, although VIP action may be important for the antiinflammatory actions of GLP-2, the Vip gene is not required for induction of a gene expression program linked to small bowel growth after enhancement of GLP-2 receptor signaling.

scholarly journals Glucagon-Like Peptide-2 Activates β-Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 291-301 ◽  
Author(s):  
Philip E. Dubé ◽  
Katherine J. Rowland ◽  
Patricia L. Brubaker
Keyword(s):  
Cell Proliferation ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Crypt Cell ◽  
Acute Administration ◽  
Intestinal Crypt ◽  
Crypt Cell Proliferation ◽  
Igf I ◽  
Glucagon Like Peptide ◽  
Crypt Cells

Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because β-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly2-GLP-2 or LR3-IGF-I (positive control) for 0.5–4 h. Nuclear translocation of β-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3β and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased β-catenin nuclear translocation in non-Paneth crypt cells by 72 ± 17% (P < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 ± 20 and 376 ± 170%, respectively (P < 0.05–0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates β-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in β-catenin.

Vitamin A deficiency inhibits intestinal adaptation by modulating apoptosis, proliferation, and enterocyte migration

2003 ◽  
Vol 285 (2) ◽  
pp. G424-G432 ◽  
Author(s):  
Deborah A. Swartz-Basile ◽  
Lihua Wang ◽  
Yuzhu Tang ◽  
Henry A. Pitt ◽  
Deborah C. Rubin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Bowel ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Intestinal Adaptation ◽  
Collagen Iv ◽  
Crypt Cell ◽  
Migration Rates ◽  
Crypt Cell Proliferation ◽  
Extracellular Matrix Components

In a prior study, vitamin A-deficient rats subjected to submassive small bowel resections did not mount a normal intestinal adaptive response by 10 days postoperatively, although adaptive increases in crypt cell proliferation were not attenuated and there were no differences in apoptotic indexes. The present study was designed to address the mechanisms by which vitamin A status effects adaptation by analyzing proliferation, apoptosis, and enterocyte migration in the early postoperative period (16 and 48 h) in vitamin A-sufficient, -deficient, and partially replenished sham-resected and resected rats. At 16 h postresection, apoptosis was significantly greater in the remnant ileum of resected vitamin A-deficient rats compared with the sufficient controls. Crypt cell proliferation was increased by resection in all dietary groups at both timepoints. However, at 48 h postresection, proliferation was significantly decreased in the vitamin A-deficient and partially replenished rats. By 48 h after resection, vitamin A deficiency also reduced enterocyte migration rates by 44%. This occurred in conjunction with decreased immunoreactive collagen IV at 48 h and 10 days postoperation. Laminin expression was also reduced by deficiency at 10 days postresection, whereas fibronectin and pancadherin were unchanged at 48 h and 10 days. These studies indicate that vitamin A deficiency inhibits intestinal adaptation following partial small bowel resection by reducing crypt cell proliferation, by enhancing early crypt cell apoptosis, and by markedly reducing enterocyte migration rates, which may be related to changes in the expression of collagen IV and other extracellular matrix components.

scholarly journals Intestinal growth-promoting properties of glucagon-like peptide-2 in mice

1997 ◽  
Vol 273 (1) ◽  
pp. E77-E84 ◽  
Author(s):  
C. H. Tsai ◽  
M. Hill ◽  
S. L. Asa ◽  
P. L. Brubaker ◽  
D. J. Drucker
Keyword(s):  
Cell Proliferation ◽  
Fold Increase ◽  
Crypt Cell ◽  
Saline Control ◽  
Intestinal Epithelial ◽  
Intestinal Growth ◽  
Crypt Cell Proliferation ◽  
Term Administration ◽  
Glucagon Like Peptide

Glucagon-like peptide-2 (GLP-2) has been shown to promote intestinal epithelial proliferation. We studied crypt cell proliferation, enterocyte cell death, and feeding behavior in GLP-2-treated mice. GLP-2 had no effect on food consumption [7.7 +/- 0.3 vs. 8.0 +/- 0.4 g/day, saline (control) vs. GLP-2-treated mice, P = not significant]; however, GLP-2 increased the crypt cell proliferation rate (46.0 +/- 1 vs. 57 +/- 5%, control vs. GLP-2, P < 0.01) and decreased the enterocyte apoptotic rate (5.9 +/- 0.7 vs. 2.8 +/- 0.2% apoptotic cells, control vs. GLP-2, P < 0.05) in small bowel (SB) epithelium. GLP-2 induced a significant increase in SB weight (1.3- to 1.75-fold increase over control, P < 0.05 to P < 0.001) in mice 1-24 mo of age. Increased SB weight was maintained after daily administration of GLP-2 to mice for 12 wk, and cessation of GLP-2 administration in older mice led to regression of (increased) SB weight and mucosal height. These observations suggest that GLP-2 regulates both cell proliferation and apoptosis and promotes intestinal growth after both short- and long-term administration in vivo.

Interleukin-10-independent anti-inflammatory actions of glucagon-like peptide 2

2008 ◽  
Vol 295 (6) ◽  
pp. G1202-G1210 ◽  
Author(s):  
Catherine P. A. Ivory ◽  
Laurie E. Wallace ◽  
Donna-Marie McCafferty ◽  
David L. Sigalet
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Lamina Propria ◽  
Interleukin 10 ◽  
Crypt Cell ◽  
Intestinal Epithelial ◽  
Crypt Cell Proliferation ◽  
Tnf Α ◽  
Glucagon Like Peptide ◽  
Anti Inflammatory

Glucagon-like peptide 2 (GLP-2) is an important intestinal growth factor with anti-inflammatory activity. We hypothesized that GLP-2 decreases mucosal inflammation and the associated increased epithelial proliferation by downregulation of Th1 cytokines attributable to reprogramming of lamina propria immune regulatory cells via an interleukin-10 (IL-10)-independent pathway. The effects of GLP-2 treatment were studied using the IL-10-deficient (IL-10−/−) mouse model of colitis. Wild-type and IL-10−/− mice received saline or GLP-2 (50 μg/kg sc) treatment for 5 days. GLP-2 treatment resulted in significant amelioration of animal weight loss and reduced intestinal inflammation as assessed by histopathology and myeloperoxidase levels compared with saline-treated animals. In colitis animals, GLP-2 treatment also reduced crypt cell proliferation and crypt cell apoptosis. Proinflammatory (IL-1β, TNF-α, IFN-γ,) cytokine protein levels were significantly reduced after GLP-2 treatment, whereas IL-4 was significantly increased and IL-6 production was unchanged. Fluorescence-activated cell sorting analysis of lamina propria cells demonstrated a decrease in the CD4+ T cell population following GLP-2 treatment in colitic mice and an increase in CD11b+/F4/80+ macrophages but no change in CD25+FoxP3 T cells or CD11c+ dendritic cells. In colitis animals, intracellular cytokine analysis demonstrated that GLP-2 decreased lamina propria macrophage TNF-α production but increased IGF-1 production, whereas transforming growth factor-β was unchanged. GLP-2-mediated reduction of crypt cell proliferation was associated with an increase in intestinal epithelial cell suppressor of cytokine signaling (SOCS)-3 expression and reduced STAT-3 signaling. This study shows that the anti-inflammatory effects of GLP-2 are IL-10 independent and that GLP-2 alters the mucosal response of inflamed intestinal epithelial cells and macrophages. In addition, the suggested mechanism of the reduction in inflammation-induced proliferation is attributable to GLP-2 activation of the SOCS-3 pathway, which antagonizes the IL-6-mediated increase in STAT-3 signaling.

scholarly journals Glucagon-Like Peptide-2 Requires a Full Complement of Bmi-1 for Its Proliferative Effects in the Murine Small Intestine

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2660-2670 ◽  
Author(s):  
Bradley R. Smither ◽  
Hilary Y. M. Pang ◽  
Patricia L. Brubaker
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Leukemia Virus ◽  
B Cell Lymphoma ◽  
Crypt Cell ◽  
Crypt Cell Proliferation ◽  
Full Complement ◽  
Glucagon Like Peptide ◽  
Long Acting ◽  
And Function

The intestinal hormone, glucagon-like peptide-2 (GLP-2), stimulates growth, survival, and function of the intestinal epithelium through increased crypt cell proliferation, and a long-acting analog has recently been approved to enhance intestinal capacity in patients with short bowel syndrome. The goal of the present study was to determine whether GLP-2-induced crypt cell proliferation requires a full complement of B-cell lymphoma Moloney murine leukemia virus insertion region-1 homolog (Bmi-1), using the Bmi-1eGFP/+ mouse model in comparison with age- and sex-matched Bmi-1+/+ littermates. Bmi-1 is a member of the polycomb-repressive complex family that promotes stem cell proliferation and self-renewal and is expressed by both stem cells and transit-amplifying (TA) cells in the crypt. The acute (6 h) and chronic (11 d) proliferative responses to long-acting human (Gly2)GLP-2 in the crypt TA zone, but not in the active or reserve stem cell zones, were both impaired by Bmi-1 haploinsufficiency. Similarly, GLP-2-induced crypt regeneration after 10-Gy irradiation was reduced in the Bmi-1eGFP/+ animals. Despite these findings, chronic GLP-2 treatment enhanced overall intestinal growth in the Bmi-1eGFP/+ mice, as demonstrated by increases in small intestinal weight per body weight and in the length of the crypt-villus axis, in association with decreased apoptosis and an adaptive increase in crypt epithelial cell migration rate. The results of these studies therefore demonstrate that a full complement of Bmi-1 is required for the intestinal proliferative effects of GLP-2 in both the physiological and pathological setting, and mediates, at least in part, the proliferation kinetics of cells in the TA zone.

Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice

Gut ◽  
2008 ◽  
Vol 59 (2) ◽  
pp. 186-196 ◽  
Author(s):  
Xiaoling Jin ◽  
Teresa A Zimmers ◽  
Zongxiu Zhang ◽  
Robert H Pierce ◽  
Leonidas G Koniaris
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Small Bowel ◽  
Interleukin 6 ◽  
Crypt Cell ◽  
Parp Cleavage ◽  
High Dose ◽  
Crypt Cell Proliferation ◽  
In Vivo Effects

Background and aimsInterleukin-6 (IL-6) is a well-recognised mediator of liver disease and regeneration. However, the in vivo effects of IL-6 on enterocytes and the intestinal tract have not been elucidated. We sought to determine the in vivo effects of IL-6 on enterocytes.MethodsMurine models of increased or absent IL-6 were examined.ResultsSystemic, high-dose IL-6 administration to mice over 7–10 days resulted in intestinal hyperplasia with a ∼40% increase in small bowel mass and in intestinal villus height. No increase in crypt cell proliferation was noted. IL-6 administration was associated with induction of pSTAT3 in enterocytes along the lower and middle regions of villi but not in crypts. IL-6 administration was also associated with induction of anti-apoptotic proteins including pAKT, and FLIP along with decreased executor caspase activity and PARP cleavage. Pulse bromodeoxyuridine labelling demonstrated equivalent crypt cell proliferation rates but prolonged enterocyte lifespan and slowed enterocyte migration rates in IL-6 treated mice. Furthermore, IL-6 treated mice showed less intestinal injury and improved barrier function following ischaemia reperfusion of the small bowel. Conversely, Il6 null mice exhibited impaired recovery following massive enterectomy and increased apoptosis after 5-fluorouracil chemotherapy relative to wild-type controls.ConclusionsIL-6 inhibited both constitutive and induced enterocyte cell death in vivo. Loss of IL-6 in mice resulted in increased activation of pro-apoptotic and necrotic pathways in enterocytes after injury. Therapies that augment IL-6 or its signalling pathways may help manage intestinal disorders associated with increased apoptosis, necrosis and gut injury.

scholarly journals Rack1 function in intestinal epithelia: regulating crypt cell proliferation and regeneration and promoting differentiation and apoptosis

2018 ◽  
Vol 314 (1) ◽  
pp. G1-G13 ◽  
Author(s):  
Zhuan-Fen Cheng ◽  
Reetesh K. Pai ◽  
Christine A. Cartwright
Keyword(s):  
Cell Proliferation ◽  
Paneth Cell ◽  
Cell Cycle Checkpoints ◽  
Crypt Cell ◽  
Colon Cells ◽  
Intestinal Epithelia ◽  
Crypt Cell Proliferation ◽  
Crypt Cells

Previously, we showed that receptor for activated C kinase 1 (Rack1) regulates growth of colon cells in vitro, partly by suppressing Src kinase activity at key cell cycle checkpoints, in apoptotic and cell survival pathways and at cell-cell adhesions. Here, we generated mouse models of Rack1 deficiency to assess Rack1’s function in intestinal epithelia in vivo. Intestinal Rack1 deficiency resulted in proliferation of crypt cells, diminished differentiation of crypt cells into enterocyte, goblet, and enteroendocrine cell lineages, and expansion of Paneth cell populations. Following radiation injury, the morphology of Rack1-deleted small bowel was strikingly abnormal with development of large polypoid structures that contained many partly formed villi, numerous back-to-back elongated and regenerating crypts, and high-grade dysplasia in surface epithelia. These abnormalities were not observed in Rack1-expressing areas of intestine or in control mice. Following irradiation, apoptosis of enterocytes was strikingly reduced in Rack1-deleted epithelia. These novel findings reveal key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. NEW & NOTEWORTHY Our findings reveal novel functions for receptor for activated C kinase 1 (Rack1) in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia.

Gut Hypertrophy After Gastric Bypass Is Associated With Increased Glucagon-Like Peptide 2 and Intestinal Crypt Cell Proliferation

2010 ◽  
Vol 252 (1) ◽  
pp. 50-56 ◽  
Author(s):  
Carel W. le Roux ◽  
Cynthia Borg ◽  
Katharina Wallis ◽  
Royce P. Vincent ◽  
Marco Bueter ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Gastric Bypass ◽  
Crypt Cell ◽  
Intestinal Crypt ◽  
Crypt Cell Proliferation ◽  
Glucagon Like Peptide ◽  
Intestinal Crypt Cell

Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome

2007 ◽  
Vol 292 (6) ◽  
pp. G1559-G1569 ◽  
Author(s):  
Lihua Wang ◽  
Yuzhu Tang ◽  
Deborah C. Rubin ◽  
Marc S. Levin
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Retinoic Acid ◽  
Small Bowel ◽  
Vitamin A ◽  
Short Bowel Syndrome ◽  
Crypt Cell ◽  
Short Bowel ◽  
Trophic Effects ◽  
Crypt Cell Proliferation

Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin β3 levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.

Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection

2006 ◽  
Vol 290 (6) ◽  
pp. G1280-G1288 ◽  
Author(s):  
Yuzhu Tang ◽  
Elzbieta A. Swietlicki ◽  
ShuJun Jiang ◽  
Kim K. Buhman ◽  
Nicholas O. Davidson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Bowel ◽  
Surface Area ◽  
Intestinal Adaptation ◽  
Critical Role ◽  
Intestinal Resection ◽  
Crypt Cell ◽  
Epithelial Migration ◽  
Crypt Cell Proliferation ◽  
Hh Signaling

The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine, but their role in the mature small bowel is unclear. With the use of a model of intestinal adaptation following partial small bowel resection, the role of Hh signaling in the adult gut was examined by determining the effects of blocking Hh signaling on the regenerative response following loss of functional surface area. Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was twofold more abundant than Gli1 and Gli2 and that bone morphogenetic protein ( BMP) 2 was most highly expressed compared with BMP1, - 4, and - 7. Following intestinal resection, the expression of Hh, Patched, Gli, and most BMP genes was markedly downregulated in the remnant ileum, and, in anti-Hh antibody-treated mice, expression of Patched 2 and Gli 1 was further suppressed. In Hh antibody-treated mice following resection, the enterocyte migration rate from crypt to villus tip was increased, and by 2 wk postoperation, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height, and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.

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