Role of central glucagon-like peptide-1 in stress regulation

Physiol Behav. 2013 Oct 2;122:201-7. doi: 10.1016/j.physbeh.2013.04.003. Epub 2013 Apr 24.


Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In the brain, the primary locus of GLP-1 production is in the caudal nucleus of the solitary tract (NTS) and the ventrolateral medulla of the hindbrain. GLP-1 immunoreactive fibers directly innervate hypophysiotrophic corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), placing GLP-1 in prime position to integrate hypothalamo-pituitary-adrenocortical responses. Exogenous central GLP-1 activates HPA axis stress responses, and responses to a variety of stressors can be blocked by a GLP-1 receptor (GLP-1R) antagonist, confirming an excitatory role in glucocorticoid secretion. In addition, central infusion of GLP-1R agonist increases heart rate and blood pressure, and activates hypothalamic and brainstem neurons innervating sympathetic preganglionic neurons, suggesting a sympathoexcitatory role of GLP-1 in the CNS. Bioavailability of preproglucagon (PPG) mRNA and GLP-1 peptide is reduced by exogenous or endogenous glucocorticoid secretion, perhaps as a mechanism to reduce GLP-1-mediated stress excitation. Altogether, the data suggest that GLP-1 plays a key role in activation of stress responses, which may be connected with its role in central regulation of energy homeostasis.

Keywords: Anxiety; Chronic stress; HPA axis; Nucleus of the solitary tract; Paraventricular nucleus; Preproglucagon.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / physiology*
  • Hypothalamo-Hypophyseal System / metabolism*
  • Pituitary-Adrenal System / metabolism*
  • Stress, Physiological / physiology*
  • Stress, Psychological / metabolism*


  • Glucagon-Like Peptide 1