title: Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice.
abstract: Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of IGF-I, and IGF-I action is modulated by IGF binding proteins (IGFBP). Our objective was to evaluate whether the intestinal response to GLP-2 or IGF-I is dependent on expression of IGFBP-3 and -5. Male, adult mice in six treatment groups, three wild-type (WT) and three double IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g body wt), IGF-I (4 μg/g body wt), or PBS (vehicle) for 7 days. IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater body weight and relative mass of visceral organs, compared with WT mice (P < 0.001). WT mice showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not stimulate jejunal growth, crypt mitosis, sucrase activity, and IGF-I receptor (IGF-IR) expression, suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt mitosis, villus height, and crypt depth that was associated with increased expression of the ErbB ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the mucosal growth induced by GLP-2.
authors.affiliation: Department of Nutritional Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Sangita G
authors.initials: SG
authors.lastname: Murali
authors.forename: Adam S
authors.initials: AS
authors.lastname: Brinkman
authors.forename: Patrick
authors.initials: P
authors.lastname: Solverson
authors.forename: Wing
authors.initials: W
authors.lastname: Pun
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.forename: Denise M
authors.initials: DM
authors.lastname: Ney
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D003106:Colon / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development; D018815:Genes, erbB / Q000502:physiology; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000502:physiology*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000254:growth & development; D007421:Intestine, Small / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development; D007422:Intestines / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development; D007668:Kidney / Q000254:growth & development; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000254:growth & development
chemical_list: D053767:Glucagon-Like Peptide 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D012313:RNA; D007334:Insulin-Like Growth Factor I