Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation

Cell Metab. 2011 Mar 2;13(3):320-30. doi: 10.1016/j.cmet.2011.02.001.


Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Animals
  • Body Weight / drug effects
  • Butadienes / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Eating*
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Male
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nitriles / pharmacology
  • Peptides / pharmacology
  • Phosphorylation
  • Protein Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / metabolism*
  • Signal Transduction*
  • Solitary Nucleus / metabolism*
  • Venoms / pharmacology


  • Butadienes
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Nitriles
  • Peptides
  • Receptors, Glucagon
  • U 0126
  • Venoms
  • Exenatide
  • Protein Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • AMP-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinase Kinases