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Neuroendocrine Function and Response to Stress in Mice with Complete Disruption of Glucagon-Like Peptide-1 Receptor Signaling¹

Departments of Reproductive Science (N.J.M., J.K.), Medicine (S.C., L.S., J.S., D.J.D.), Psychiatry (F.V.), and Laboratory Medicine and Pathobiology (S.L.A.), Toronto General Hospital (S.C., L.S., J.S., D.J.D.), Center for Addiction and Mental Health (F.V.), Mount Sinai Hospital (S.L.A.), and the Banting and Best Diabetes Center (S.C., L.S., J.S., D.J.D.), University of Toronto, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. D. Drucker, Toronto General Hospital, 200 Elizabeth Street CCRW3–838, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca

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.

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