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Title: GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets

Author
item Burrin, Douglas - Doug
item STOLL, BARBARA - BAYLOR COLLEGE MED
item GUAN, XINFU - BAYLOR COLLEGE MED
item CUI, LIWEI - BAYLOR COLLEGE MED
item CHANG, XIAOYAN - BAYLOR COLLEGE MED
item Hadsell, Darryl

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2006
Publication Date: 1/1/2007
Citation: Burrin, D.G., Stoll, B., Guan, X., Cui, L., Chang, X., Hadsell, D. 2007. GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets. American Journal of Physiology - Endocrinology and Metabolism. 292:E281-E291

Interpretive Summary: The growth and development of the gut is a key function that is poorly developed in premature infants. These infants often require intravenous nutrition, called total parenteral nutrition (TPN), since they cannot be fed orally. We previously showed that TPN retards intestinal growth and development in neonatal piglets, which are used as a model for human premature infants. We also showed that secretion of a key gut growth factor, called glucagon-like peptide 2 (GLP-2), is reduced during TPN. In the current study, our aim was to determine the short-term changes in intestinal growth when the growth factor GLP-2 is infused intravenously in TPN-fed piglets. We studied piglets given TPN or GLP-2 for 1, 4, or 48 hr and then measured endpoints of intestinal growth. We found that intestinal growth was only increased after 48 hr of GLP-2 treatment. However, we found that activation of cellular signals that lead to intestinal cell growth and inhibition of cell death were activated rapidly within 1-4 hr after GLP-2 treatment. We also found that some of the key signals activated by GLP-2 were localized to cells that line the intestinal wall, called epithelial cells. This study provides important information regarding how quickly GLP-2 stimulates intestinal growth and may be useful for the design of treatment regimens to be used in infants.

Technical Abstract: We previously demonstrated the dose-dependent glucagon-like peptide (GLP)-2 activation of intracellular signals associated with increased epithelial cell survival and proliferation in the neonatal intestine. Our current aim was to quantify the acute, temporal GLP-2 activation of these key intracellular signals and relate this to changes in epithelial cell survival and proliferation in the neonatal intestine. We studied 29 total parenteral nutrition-fed neonatal piglets infused intravenously with either saline (control) or human GLP-2 (420 micromol.kg(-1).h(-1)) for 1, 4, or 48 h. GLP-2 infusion increased small intestinal weight, DNA and protein content, and villus height at 48 h, but not at 1 or 4 h. Intestinal crypt and villus apoptosis decreased and crypt cell proliferation and protein synthesis increased linearly with duration of GLP-2 infusion, but were statistically different from controls only after 48 h. Before the morphological and cellular kinetic changes, GLP-2 rapidly activated putative GLP-2 receptor downstream signals within 1-4 h, including phosphorylation of protein kinase A, protein kinase B, extracellular signal-regulated kinase 1/2, and the transcription factors cAMP response element-binding protein and c-Fos. GLP-2 rapidly suppressed caspase-3 activation and upregulated Bcl-2 abundance within 1 h, whereas there was an increase in apoptosis inhibitors X-linked inhibitor of apoptosis at 1 h and cellular inhibitor of apoptosis-2 at 4 and 48 h. We also show that the increased c-Fos and reduced active caspase-3 immunostaining after GLP-2 infusion was localized in epithelial cells. We conclude that GLP-2-induced activation of intracellular signals involved in both cell survival and proliferation occurs rapidly and precedes the trophic cellular kinetic effects that occur later in intestinal epithelial cells.