ABSTRACT
Intestinal proglucagon is thought to be synthesized primarily by the distal gut, although the role of proglucagon-derived glucagon-like peptide I (GLP-I) as a major physiological incretin would seem to be associated with production in proximal small bowel. To better characterize the sites of production of proglucagon and GLP-I in the small intestine and evaluate nutrient regulation of small bowel proglucagon and derived peptides, we evaluated the effects of fasting for 72 h and subsequent refeeding or jejunal infusion of long-chain triglyceride (LCT) for 24 h on local expression of proglucagon in proximal and distal small bowel. Proglucagon mRNA abundance and cellular localization were determined and correlated with wet weight of bowel. In jejunum, proglucagon mRNA abundance decreased by 40% with fasting (P < 0.005) and increased with refeeding to levels similar to those of ad libitum-fed animals. In ileum, fasting resulted in a 20% decrease in proglucagon mRNA (P < 0.005); in contrast to jejunum, refeeding did not result in a significant rise in ileal proglucagon mRNA abundance from fasting values. In jejunum, signal intensity of proglucagon mRNA per cell, determined by in situ hybridization, decreased with fasting (P < 0.05) and increased with refeeding (P < 0.005) in proportion to changes in mRNA abundance. Plasma enteroglucagon and GLP-I levels correlated with jejunal proglucagon mRNA. Intrajejunal infusion of LCT increased expression of proglucagon to a greater extent in jejunum than in ileum. In conclusion, enteral nutrient intake stimulates small bowel proglucagon expression; this effect is greater in jejunum than ileum, consistent with greater intraluminal nutrient exposure and the role of jejunum as a source of the major incretin GLP-I.
Subject(s)
Eating , Fasting , Gene Expression , Glucagon/biosynthesis , Ileum/metabolism , Jejunum/metabolism , Peptide Fragments/biosynthesis , Protein Precursors/biosynthesis , Triglycerides/metabolism , Triglycerides/pharmacology , Animals , Blotting, Northern , Gene Expression/drug effects , Glucagon/analysis , Glucagon-Like Peptide 1 , In Situ Hybridization , Male , Peptide Fragments/analysis , Proglucagon , Protein Precursors/analysis , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , RNA, Ribosomal, 28S/analysis , RNA, Ribosomal, 28S/biosynthesis , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Regression AnalysisABSTRACT
Insulin-like growth factor-I (IGF-I) may regulate small bowel growth. Analyses here in ad libitum-fed, fasted, and refed rats demonstrate that during fasting and refeeding changes in jejunal mass correlate with changes in serum IGF-I and jejunal IGF-I mRNAs. These data indicate that circulating and locally expressed IGF-I contribute to nutrient regulation of jejunal mass. During refeeding, jejunal IGF binding protein 3 (IGFBP-3) mRNA abundance was reduced relative to that of IGF-I, possibly amplifying enterotrophic actions of IGF-I. Localization of IGFBP-3 to subepithelial cells in lamina propria of jejunum indicates that IGFBP-3 derived from lamina propria may modulate IGF-I action on adjacent epithelium. Ileum differed from jejunum in that refeeding did not increase bowel mass or IGF-I mRNA to ad libitum values. Differences in exposure to luminal nutrient may underlie distinct responses of the two segments. Rats fed elemental diet intravenously showed reduced jejunal mass but not reduced jejunal IGF-I mRNA compared with rats fed oral elemental diet. Elemental nutrient given intravenously or orally therefore does not differ in effects on jejunal IGF-I expression. Complex luminal nutrient may, however, regulate jejunal IGF-I expression.
