title: IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine.
abstract: Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone that stimulates the growth of the intestinal epithelium. We have previously demonstrated that GLP-2 exerts its intestinotropic effect through an indirect mechanism that requires both IGF-1 and the intestinal epithelial IGF-1 receptor. However, the biological activity of IGF-1 is modulated by IGF binding proteins (IGFBPs), including IGFBP-4, which is highly expressed in the intestine. To determine the role of IGFBP-4 in the tropic effects of GLP-2, IGFBP-4 knockout (KO) and control mice were treated with degradation-resistant GLP-2 or vehicle for 10 days. Comparable levels of IGFBP-1-3/5-7 mRNAs were observed in the intestinal mucosa of all animals. IGFBP-4 KO mice had greater small intestinal weight and length, and deeper crypts (P < .05) as compared with controls, suggesting that IGFBP-4 has an inhibitory role in basal intestinal growth. However, small intestinal weight, crypt-villus height and crypt cell proliferation increased in response to GLP-2 in control mice (P < .05), and these changes were abrogated with IGFBP-4 KO. In contrast, pregnancy-associated plasma protein-A KO mice, which have increased levels of circulating IGFBP-4, demonstrated a normal intestinotropic response to GLP-2. Finally, GLP-2 treatment of control mice significantly increased IGFBP-4 mRNA expression in the jejunal mucosa (P < .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10(-8)M for 2 h; P < .05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2.
authors.affiliation: Departments of Physiology (K.A., N.A.I., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Department of Neuroscience and Cell Biology (J.E.P.), Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Kaori
authors.initials: K
authors.lastname: Austin
authors.forename: Nuvair A
authors.initials: NA
authors.lastname: Imam
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000254:growth & development* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D017208:Rats, Wistar
chemical_list: D053767:Glucagon-Like Peptide 2; D018974:Insulin-Like Growth Factor Binding Protein 4