Characterization of Intestinal and Pancreatic Dysfunction in VPAC1-Null Mutant Mouse

Fabricius, Dorit; Karaçay, Bahri; Shutt, Damon C.; Leverich, Whitney; Schafer, Blanca; Takle, Erika J; Thedens, Daniel; Khanna, Geetika; Raikwar, Sudhanshu P.; Yang, Baoli; Desmond, Mary E.; O’Dorisio, M. Sue

doi:10.1097/mpa.0b013e318214c783

Cited by 33 publications

(33 citation statements)

References 74 publications

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“…This was confirmed in fasted rats by the administration of the VIP antagonist, [Lsy1, Pro2,5, Arg3,4,Tyr6]-VIP, which inhibited food intake-induced increase of plasmatic ACTH and corticosterone (Alexander, 1995). Conversely, VPAC1 receptors were not found to mediate lipolysis or significantly affect adipogenesis in vitro (Akesson, 2005; Sheward, 2007), but VPAC1 homozygous mutant knockout mice presented developmental delay and reduced body growth and weight, similar to our VIP−/− mice (Fabricius, 2011). However, a comprehensive study on body composition including lean and fat mass analysis has never been performed in VPAC1 knockout mice.…”

Section: Discussionsupporting

confidence: 62%

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

Larauche

Flores

et al. 2015

J Mol Neurosci

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Introduction Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide that belongs to the secretin-glucagon superfamily of peptides and has 68% homology with PACAP. VIP is abundantly expressed in the central and peripheral nervous system and in the gastrointestinal tract, where it exercises several physiological functions. Previously, it has been reported that VIP regulates feeding behavior centrally in different species of vertebrates such as goldfishes, chicken, and rodents. Additional studies are necessary to analyze the role of endogenous VIP on the regulation of appetite/satiety together with feeding behavior, metabolic hormone release, body mass composition and energy balance. Aims To elucidate the physiological pathways by which VIP regulates appetite/satiety, feeding behavior, metabolic hormones and body mass composition. Methods VIP deficient (VIP −/−) and age-matched wild-type (WT) littermates were weekly monitored from 5 to 22 weeks of age using a whole body composition EchoMRI analyzer. Food intake and feeding behavior were analyzed using the BioDAQ automated monitoring system. Plasma levels of metabolic hormones including active-ghrelin, GLP-1, leptin, PYY, pancreatic polypeptide (PP), adiponectin, and insulin were measured in fasting as well as in postprandial conditions. Results The genetic lack of VIP led to a significant reduction of body weight and fat mass and to an increase of lean mass as the mice aged. Additionally, VIP−/− mice had a disrupted pattern of circadian feeding behavior resulting in an abolished regular nocturnal/diurnal feeding. These changes were associated with an altered secretion of adiponectin, GLP-1, leptin, PYY and insulin in VIP−/− mice. Our data demonstrates that endogenous VIP is involved in the control of appetite/satiety, feeding behavior, body mass composition and in the secretion of six different key regulatory metabolic hormones. Conclusions Our data show that endogenous VIP is involved in the control of appetite/satiety, feeding behavior, body mass composition and in the secretion of six key regulatory metabolic hormones. VIP plays a key role in the regulation of body weight and mass composition phenotype by significantly enhancing body weight and fat mass accumulation. Therefore, VIP signaling is critical for the modulation of appetite/satiety and body mass phenotype and is suggested to be a target for future treatment of obesity.

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Section: Discussionsupporting

confidence: 62%

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

Larauche

Flores

et al. 2015

J Mol Neurosci

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“…Moreover, older Vip Ϫ/Ϫ mice appeared susceptible to the development of intestinal obstruction. Genetic elimination of the VIP receptor type 1 (VPAC1) gene results in impaired neonatal growth, increased mortality of mice around the time of weaning, and increased mucosal cell proliferation and thickening of the bowel wall, detected in mice analyzed at 8 wk of age (40). In contrast, although VPAC2 knockout mice exhibit enhanced susceptibility to DS-induced colitis (41), a detailed analysis of the basal phenotype of the VPAC2 Ϫ/Ϫ small bowel has not yet been reported.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2012

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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.

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“…Reduced lumen expansion and/or atresia of the intestine have been found in Vip -, Vipr1 - and Cftr -null animals (Fabricius et al, 2011; Hodges et al, 2008; Lelievre et al, 2007; Meyerholz et al, 2010). Similarly, we show that formation of the ductal network in salivary gland derived from Cftr -null mice is impaired (Figure 7H).…”

Section: Discussionmentioning

confidence: 99%

Parasympathetic Innervation Regulates Tubulogenesis in the Developing Salivary Gland

et al. 2014

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A fundamental question in development is how cells assemble to form a tubular network during organ formation. In glandular organs tubulogenesis is a multistep process requiring coordinated proliferation, polarization and reorganization of epithelial cells to from a lumen, and lumen expansion. Although it is clear that epithelial cells possess an intrinsic ability to organize into polarized structures, the mechanisms coordinating morphogenetic processes during tubulogenesis are poorly understood. Here, we demonstrate that parasympathetic nerves regulate ductal tubulogenesis in the developing salivary gland. We show that the neurotransmitter vasoactive intestinal peptide (VIP) secreted by the innervating ganglia promotes ductal growth, leads to the formation of a contiguous lumen, and facilitates lumen expansion through a cAMP/PKA-dependent pathway. Furthermore, we provide evidence that lumen expansion is independent of apoptosis and involves the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated Cl(−) channel. Thus, parasympathetic innervation coordinates multiple steps in tubulogenesis during organ formation.

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Characterization of Intestinal and Pancreatic Dysfunction in VPAC1-Null Mutant Mouse

Abstract: These observations support a role for VPAC1 during embryonic and neonatal development of intestines and endocrine pancreas.

Cited by 33 publications

References 74 publications

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

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

Parasympathetic Innervation Regulates Tubulogenesis in the Developing Salivary Gland

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