Hypothalamic preproghrelin gene expression is repressed by insulin via both PI3-K/Akt and ERK1/2 MAPK pathways in immortalized, hypothalamic neurons

Neuroendocrinology. 2009;89(3):267-75. doi: 10.1159/000167698. Epub 2008 Oct 29.

Abstract

The gut peptide ghrelin is expressed within neurons of the hypothalamus. Using a hypothalamic cell line, mHypoE-38 neurons, the effect of insulin on preproghrelin gene expression was assayed. These cells contain neuron-specific markers, preproghrelin and the insulin receptor. We determined that insulin has direct effects on preproghrelin gene expression. Insulin (10 nM) stimulated protein kinase B (Akt) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation from 5 to 60 min and 5 min, respectively, and led to repression of preproghrelin gene expression at 2 h. Pharmacological inhibitors to phosphoinositide-3-kinase (PI3-K; LY294002) and MEK (PD98059) demonstrated that basal ghrelin gene expression is regulated by the PI3-K pathway and requires the mitogen-activated protein kinase pathway for insulin-stimulated preproghrelin repression. These results demonstrate that insulin has a direct effect on hypothalamic neurons to decrease preproghrelin gene expression through classic insulin pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chromones / pharmacology
  • Down-Regulation*
  • Flavonoids / pharmacology
  • Ghrelin / genetics*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Insulin / pharmacology*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morpholines / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, Insulin / agonists*
  • Receptor, Insulin / metabolism

Substances

  • Chromones
  • Flavonoids
  • Ghrelin
  • Insulin
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one