Endogenous Glucagon-like Peptide-1 Suppresses High-Fat Food Intake by Reducing Synaptic Drive onto Mesolimbic Dopamine Neurons

Cell Rep. 2015 Aug 4;12(5):726-33. doi: 10.1016/j.celrep.2015.06.062. Epub 2015 Jul 23.

Abstract

Glucagon-like peptide-1 (GLP-1) and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS), which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. Using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA) and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA) neurons within the VTA that project to the nucleus accumbens (NAc) medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling.

Publication types

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

MeSH terms

  • Animals
  • Dietary Fats*
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / metabolism*
  • Eating / physiology*
  • Glucagon-Like Peptide 1 / metabolism*
  • Mice
  • Mice, Transgenic
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / metabolism
  • Signal Transduction / physiology
  • Synapses / metabolism*
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / metabolism*

Substances

  • Dietary Fats
  • Glucagon-Like Peptide 1