title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Yusta
authors.forename: Dianne
authors.initials: D
authors.lastname: Holland
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D000067758:Glucagon-Like Peptide-2 Receptor; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D019879:Paneth Cells / Q000187:drug effects / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D036341:Intercellular Signaling Peptides and Proteins; D018027:Receptors, Glucagon; D014660:Vasoactive Intestinal Peptide; D007334:Insulin-Like Growth Factor I