Role of central glucagon-like peptide-1 in hypothalamo-pituitary-adrenocortical facilitation following chronic stress

Exp Neurol. 2008 Apr;210(2):458-66. doi: 10.1016/j.expneurol.2007.11.016. Epub 2007 Nov 29.


Central glucagon-like peptide-1 (GLP-1) regulates food intake, glucose homeostasis, and behavioral and neuroendocrine responses to acute stress. Given its pronounced role in acute stress regulation, the GLP-1 system is a prime candidate for mediating the prolonged drive of the hypothalamo-pituitary-adrenocortical axis by chronic stress. To test this hypothesis, we evaluated the necessity and sufficiency of GLP-1 for production of chronic stress-induced changes in HPA axis function. Exogenous GLP-1 or the GLP-1 receptor antagonist, dHG-exendin, were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress (CVS) for 7 days. Animals in the CVS groups received GLP-1 or dHG-exendin immediately prior to each stress exposure. Prior to and at the end of the 7-day trial, chronically-stressed animals were subjected to a novel stressor to test for HPA axis facilitation. Neither GLP-1 nor dHG-exendin affected CVS-associated increases in adrenal weight or decreases in basal plasma glucose levels. In addition, neither exogenous GLP-1 nor dHG-exendin altered any index of HPA axis activity in unstressed rats. However, GLP-1 enhanced CVS-induced facilitation of corticosterone (but not ACTH) response to an acute stress, whereas dHG-exendin inhibited facilitation. In addition, GLP-1 decreased body weight in chronically-stressed animals. dHG-exendin increased food intake and body weight in unstressed animals, consistent with a tonic role for GLP-1 in body weight regulation. Overall, our data suggest that brain GLP-1 modulates HPA axis activity within the context of chronic stress, perhaps at the level of the adrenal gland.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Body Weight / drug effects
  • Chronic Disease
  • Corticosterone / blood
  • Disease Models, Animal
  • Eating / drug effects
  • Glucagon-Like Peptide 1 / administration & dosage*
  • Glycosaminoglycans / administration & dosage
  • Hypothalamo-Hypophyseal System / drug effects*
  • Male
  • Pituitary-Adrenal System / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Restraint, Physical / methods
  • Stress, Psychological / etiology
  • Stress, Psychological / pathology*
  • Stress, Psychological / prevention & control


  • Glycosaminoglycans
  • depolymerized holothurian glucosaminoglycan
  • Glucagon-Like Peptide 1
  • Adrenocorticotropic Hormone
  • Corticosterone