Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats.
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.
Seo
Sanghee
S
Department of Pharmacology, Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, Kyunghee University School of Medicine, Seoul, Korea.
Ju
Sunghee
S
Chung
Hyunju
H
Lee
Dahm
D
Park
Seungjoon
S
D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D004435:Eating / Q000187:drug effects; D005215:Fasting; D015870:Gene Expression / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009479:Neuropeptides / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D052216:Glucagon-Like Peptide 1; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase