Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons

Biochem Biophys Res Commun. 2014 Aug 22;451(2):276-81. doi: 10.1016/j.bbrc.2014.07.116. Epub 2014 Aug 1.

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetic patients and shown to reduce food intake and body weight. The anorexigenic effects of GLP-1 and GLP-1 receptor agonists are thought to be mediated primarily via the hypothalamic paraventricular nucleus (PVN). GLP-1, an intestinal hormone, is also localized in the nucleus tractus solitarius (NTS) of the brain stem. However, the role of endogenous GLP-1, particularly that in the NTS neurons, in feeding regulation remains to be established. The present study examined whether the NTS GLP-1 neurons project to PVN and whether the endogenous GLP-1 acts on PVN to restrict feeding. Intra-PVN injection of GLP-1 receptor antagonist exendin (9-39) increased food intake. Injection of retrograde tracer into PVN combined with immunohistochemistry for GLP-1 in NTS revealed direct projection of NTS GLP-1 neurons to PVN. Moreover, GLP-1 evoked Ca(2+) signaling in single neurons isolated from PVN. The majority of GLP-1-responsive neurons were immunoreactive predominantly to corticotropin-releasing hormone (CRH) and nesfatin-1, and less frequently to oxytocin. These results indicate that endogenous GLP-1 targets PVN to restrict feeding behavior, in which the projection from NTS GLP-1 neurons and activation of CRH and nesfatin-1 neurons might be implicated. This study reveals a neuronal basis for the anorexigenic effect of endogenous GLP-1 in the brain.

Keywords: Corticotropin-releasing hormone; Feeding; Glucagon-like peptide-1; Nesfatin-1; Nucleus tractus solitarius; Paraventricular nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Calcium-Binding Proteins / physiology*
  • Corticotropin-Releasing Hormone / physiology*
  • DNA-Binding Proteins / physiology*
  • Eating / drug effects
  • Eating / physiology*
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology
  • Glucagon-Like Peptide 1 / physiology*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Male
  • Microinjections
  • Nerve Tissue Proteins / physiology*
  • Neural Pathways / physiology
  • Neurons / physiology
  • Nucleobindins
  • Oxytocin / physiology*
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / physiology*
  • Peptide Fragments / administration & dosage
  • Rats
  • Rats, Wistar
  • Receptors, Glucagon / antagonists & inhibitors
  • Solitary Nucleus / physiology*

Substances

  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • NUCB2 protein, human
  • Nerve Tissue Proteins
  • Nucb1 protein, rat
  • Nucleobindins
  • Peptide Fragments
  • Receptors, Glucagon
  • Oxytocin
  • exendin (9-39)
  • Glucagon-Like Peptide 1
  • Corticotropin-Releasing Hormone