Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling

Endocrinology. 2000 Feb;141(2):752-62. doi: 10.1210/endo.141.2.7326.


Glucagon-like peptide-1 (GLP-1), a potent regulator of glucose homeostasis, is also produced in the central nervous system, where GLP-1 has been implicated in the neuroendocrine control of hypothalamic-pituitary function, food intake, and the response to stress. The finding that intracerebroventricular GLP-1 stimulates LH, TSH, corticosterone, and vasopressin secretion in rats prompted us to assess the neuroendocrine consequences of disrupting GLP-1 signaling in mice in vivo. Male GLP-1 receptor knockout (GLP-1R-/-) mice exhibit reduced gonadal weights, and females exhibit a slight delay in the onset of puberty; however, male and female GLP-1R-/- animals reproduce successfully and respond appropriately to fluid restriction. Although adrenal weights are reduced in GLP-1R-/- mice, hypothalamic CRH gene expression and circulating levels of corticosterone, thyroid hormone, testosterone, estradiol, and progesterone are normal in the absence of GLP-1R-/- signaling. Intriguingly, GLP-1R-/- mice exhibit paradoxically increased corticosterone responses to stress as well as abnormal responses to acoustic startle that are corrected by glucocorticoid treatment. These findings suggest that although GLP-1R signaling is not essential for development and basal function of the murine hypothalamic-pituitary-adrenal axis, abrogation of GLP-1 signaling is associated with impairment of the behavioral and neuroendocrine responses to stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Adrenal Glands / growth & development
  • Aging / physiology
  • Animals
  • Body Weight
  • Corticosterone / blood
  • Corticotropin-Releasing Hormone / genetics
  • Estradiol / blood
  • Estrus
  • Female
  • Glucagon-Like Peptide-1 Receptor
  • Hypothalamus / metabolism
  • Male
  • Maze Learning / physiology*
  • Mice
  • Mice, Knockout
  • Ovary / growth & development
  • Pituitary Gland / growth & development
  • Progesterone / blood
  • Rats
  • Receptors, Glucagon / deficiency
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / physiology*
  • Reflex, Startle / physiology*
  • Sexual Maturation / physiology*
  • Stress, Physiological / blood
  • Stress, Physiological / physiopathology*
  • Testis / growth & development
  • Testosterone / blood
  • Thyroid Hormones / blood


  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Glucagon
  • Thyroid Hormones
  • Testosterone
  • Progesterone
  • Estradiol
  • Corticotropin-Releasing Hormone
  • Corticosterone