Regulation of brain insulin mRNA by glucose and glucagon-like peptide 1

Biochem Biophys Res Commun. 2008 Nov 28;376(4):694-9. doi: 10.1016/j.bbrc.2008.09.054. Epub 2008 Sep 20.

Abstract

Whether the brain synthesizes insulin is currently debated. Two clonal, immortalized mouse hypothalamic cell lines from e17, mHypoE-39 and mHypoE-46, express insulin 2 (Ins2), but not Ins1. We analyzed regions necessary for basal gene activity and found that the mouse Ins2 region -110/+183 bp stimulates promoter activity in hypothalamic neurons. The rat Ins2 showed moderate activity, whereas the human promoter construct is repressed below basal levels. In MIN6 pancreatic beta-cells, all of the Ins1 and Ins2 promoter constructs display high levels of transcriptional activity. The cell lines also express components of glucose-sensing machinery and the endogenous glucagon-like peptide 1 receptor (Glp-1R). We observed that 16.7 mM glucose induces Ins2 mRNA, while forskolin and a Glp-1 agonist, exendin-4, induce a biphasic Ins2 mRNA response in mHypoE-39 neurons. The insulin cis-regulatory regions differ between the pancreas and the hypothalamus, and glucose and Glp-1 regulate the expression of hypothalamic insulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Colforsin / pharmacology
  • Exenatide
  • Gene Expression
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Humans
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptides / pharmacology
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / biosynthesis
  • Rats
  • Venoms / pharmacology

Substances

  • Insulin
  • Peptides
  • RNA, Messenger
  • Venoms
  • Colforsin
  • Glucagon-Like Peptide 1
  • Exenatide
  • Glucose