Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

Am J Physiol Endocrinol Metab. 2012 Oct 15;303(8):E994-1005. doi: 10.1152/ajpendo.00291.2012. Epub 2012 Aug 14.


Glucagon-like peptide 2 (GLP-2) is an enteroendocrine hormone trophic for intestinal mucosa; it has been shown to increase enteric neuronal expression of vasoactive intestinal polypeptide (VIP) in vivo. We hypothesized that GLP-2 would regulate VIP expression in enteric neurons via a phosphatidylinositol-3 kinase-γ (PI3Kγ) pathway. The mechanism of action of GLP-2 was investigated using primary cultures derived from the submucosal plexus (SMP) of the rat and mouse colon. GLP-2 (10(-8) M) stimulation for 24 h increased the proportion of enteric neurons expressing VIP (GLP-2: 40 ± 6% vs. control: 22 ± 5%). GLP-2 receptor expression was identified by immunohistochemistry on neurons (HuC/D+) and glial cells (GFAP+) but not on smooth muscle or fibroblasts in culture. Over 1-4 h, GLP-2 stimulation of SMP increased phosphorylated Akt/Akt ratios 6.1-fold, phosphorylated ERK/ERK 2.5-fold, and p70S6K 2.2-fold but did not affect intracellular cAMP. PI3Kγ gene deletion or pharmacological blockade of PI3Kγ, mammalian target of rapamycin (mTOR), and MEK/ERK pathways blocked the increase in VIP expression by GLP-2. GLP-2 increased the expression of growth factors and their receptors in SMP cells in culture [IGF-1r (3.2-fold increase), EGFr (5-fold), and ErbB-2-4r (6- to 7-fold)] and ligands [IGF-I (1.5-fold), amphiregulin (2.5-fold), epiregulin (3.2-fold), EGF (7.5-fold), heparin-bound EGF (2.0-fold), β-cellulin (50-fold increase), and neuregulins 2-4 (300-fold increase) (by qRT-PCR)]. We conclude that GLP-2 acts on enteric neurons and glial cells in culture via a PI3Kγ/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, and expression of receptors and ligands for the IGF-I and ErbB pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cells, Cultured
  • ELAV Proteins / metabolism
  • Enteric Nervous System / drug effects
  • Enteric Nervous System / metabolism*
  • ErbB Receptors / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • Glucagon-Like Peptide 2 / pharmacology*
  • Immunohistochemistry
  • Mice
  • Neuregulins / metabolism
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oncogene Proteins v-erbB / biosynthesis
  • Oncogene Proteins v-erbB / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphatidylinositol 3-Kinase / physiology
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / metabolism
  • Vasoactive Intestinal Peptide / biosynthesis*


  • ELAV Proteins
  • Glial Fibrillary Acidic Protein
  • Glucagon-Like Peptide 2
  • Neuregulins
  • Oncogene Proteins v-erbB
  • Vasoactive Intestinal Peptide
  • Phosphatidylinositol 3-Kinase
  • ErbB Receptors
  • TOR Serine-Threonine Kinases