Neuroendocrine Function and Response to Stress in Mice with Complete Disruption of Glucagon-Like Peptide-1 Receptor Signaling

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 intracerebroventricu...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2000-02, Vol.141 (2), p.752-762
Main Authors: MacLusky, Neil J, Cook, Sonya, Scrocchi, Louise, Shin, Jennifer, Kim, Julie, Vaccarino, Franco, Asa, Sylvia L, Drucker, Daniel J
Format: Article
Language:English
Subjects:
17β-Estradiol
Central nervous system
Corticosterone
Corticotropin-releasing hormone
Disruption
Females
Food intake
Gene expression
Glucagon
Glucagon-like peptide 1
Glucocorticoids
Homeostasis
Hypothalamic-pituitary-adrenal axis
Hypothalamus
Luteinizing hormone
Males
Neuroendocrine system
Peptides
Pituitary
Progesterone
Puberty
Receptors
Sex hormones
Testosterone
Thyroid
Thyroid-stimulating hormone
Vasopressin
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Summary: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.
ISSN:0013-7227
1945-7170
DOI:10.1210/endo.141.2.7326