GLP-1 action in the mouse bed nucleus of the stria terminalis

Neuropharmacology. 2018 Mar 15:131:83-95. doi: 10.1016/j.neuropharm.2017.12.007. Epub 2017 Dec 6.

Abstract

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses. Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine. Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.

Keywords: BNST; Channelrhodopsin; Electrophysiology; Food intake; Glucagon-like peptide-1 receptor; PPG; Preproglucagon; Stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Dose-Response Relationship, Drug
  • Eating / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology
  • Proglucagon / metabolism
  • Quinoxalines / pharmacology
  • Septal Nuclei / cytology
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism*
  • Stress, Psychological / metabolism
  • Stress, Psychological / pathology

Substances

  • Excitatory Amino Acid Antagonists
  • Glucagon-Like Peptide-1 Receptor
  • Luminescent Proteins
  • Peptide Fragments
  • Quinoxalines
  • exendin (9-39)
  • Proglucagon
  • FG 9041
  • Glucagon-Like Peptide 1