Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats

Endocr J. 2008 Oct;55(5):867-74. doi: 10.1507/endocrj.k08e-091. Epub 2008 May 28.

Abstract

Intracerebroventricular (icv) administration of glucagon-like peptide-1 (GLP-1) inhibits food intake and induces c-fos expression in the hypothalamus. However, the effects of GLP-1 on hypothalamic neuronal activity or neuropeptide mRNA expression are unknown. In this study, we examined the effects of GLP-1 on fasting-induced changes in the expression of hypothalamic orexigenic and anorexigenic neuropeptide. Food intake was significantly inhibited after icv injection of GLP-1 in 48 h fasted rats. Hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNAs were significantly increased by fasting, whereas icv GLP-1 treatment significantly attenuated these fasting-induced increases. Both proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA levels were decreased by fasting, while GLP-1 treatment attenuated fasting-induced decreases in POMC and CART expression. We also determined the mRNA levels of AMP-activated kinase (AMPK) and found that fasting resulted in a significant stimulation of hypothalamic AMPKalpha2 mRNA. Fasting-induced increase in AMPKalpha2 mRNA was almost completely prevented by GLP-1 treatment. Analysis of phosphorylated AMPKalpha and acetyl CoA carboxylase showed similar results. Taken together, our observation suggests that the decreased food intake by GLP-1 is caused by preventing the fasting-induced increase in hypothalamic NPY and AgRP and the fasting-induced decrease in hypothalamic POMC and CART. Our results also suggest that the food intake lowering effect of GLP-1 is caused by reversing the fasting-induced increase in hypothalamic AMPK activity. Therefore we conclude that the anorectic effect of GLP-1 seems to be mediated by, at least in part, by the hypothalamus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • Acetyl-CoA Carboxylase / genetics
  • Animals
  • Eating / drug effects
  • Fasting
  • Gene Expression / drug effects*
  • Glucagon-Like Peptide 1 / administration & dosage*
  • Hypothalamus / chemistry
  • Hypothalamus / drug effects*
  • Hypothalamus / metabolism
  • Injections, Intraventricular
  • Male
  • Neuropeptides / genetics*
  • Proto-Oncogene Proteins c-fos / analysis
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Neuropeptides
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Glucagon-Like Peptide 1
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase