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The Role of Central Glucagon-Like Peptide-1 in Mediating the Effects of Visceral Illness: Differential Effects in Rats and Mice

Departments of Psychiatry (J.L.L., R.J.S.) and Medicine (D.A.D.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559; Department of Neuroscience (L.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Departments of Medicine and Neurology and Division of Endocrinology (J.K.E.), Beth Israel Deaconess Medical Center, Program in Neuroscience Harvard Medical School, Boston, Massachusetts 02215; and Department of Medicine (D.J.D.), Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada, M5G 2C4

Address all correspondence and requests for reprints to: Randy J. Seeley, Department of Psychiatry, 2170 East Galbraith Road, University of Cincinnati, Cincinnati, Ohio 45237.

In rats, central administration of glucagon-like peptide-1 (GLP-1) elicits symptoms of visceral illness like those caused by the toxin lithium chloride (LiCl), including anorexia, conditioned taste aversion (CTA) formation, and neural activation in the hypothalamus and hindbrain including activation of brainstem preproglucagon cells. Most compellingly, pharmacological antagonists of the GLP-1 receptor (GLP-1R) block several effects of LiCl in rat. The major goal of these experiments was to further test the hypothesis that the central nervous system GLP-1 system is critical to the visceral illness actions of LiCl by using mice with a targeted disruption of the only described GLP-1R. First, we observed that, like the rat, LiCl activates preproglucagon neurons in wild-type mice. Second, GLP-1R –/– mice demonstrated normal anorexic and CTA responses to LiCl. To test the possibility that alternate GLP-1Rs mediate aversive effects, we examined the ability of GLP-1 to produce a CTA in GLP1R –/– mice. Although lateral ventricular GLP-1 produced a CTA in wild-type mice, it did not produce a CTA in GLP-1R –/– mice. Furthermore, the same GLP-1R antagonist that can block the aversive effects of LiCl in the rat failed to do so in the mouse. These results support the conclusion that in mouse, unlike in rat, GLP-1R signaling is not required for the visceral illness response to LiCl. Such species differences are an important consideration when comparing results from rat and mouse studies.

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