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Fasting Inhibits the Growth and Reproductive Axes via Distinct Y2 and Y4 Receptor-Mediated Pathways

Neuroscience Research Program (S.L., E.-J.D.L., D.B., N.J.L., K.S., A.S., H.H.), Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; and Comprehensive Cancer Center (M.J.D.), The Ohio State University, Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Herbert Herzog, Neuroscience Research Program, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Sydney, Australia. E-mail: h.herzog{at}garvan.org.au.

Neuropeptide Y, a neuropeptide abundantly expressed in the brain, has been implicated in the regulation of the hypothalamo-pituitary-somatotropic axis and the hypothalamo-pituitary-gonadotropic axis. Elevated hypothalamic neuropeptide Y expression, such as that occurs during fasting, is known to inhibit both of these axes. However, it is not known which Y receptor(s) mediate these effects. Here we demonstrate, using Y receptor knockout mice, that Y2 and Y4 receptors are separately involved in the regulation of these axes. Fasting-induced inhibition of hypothalamic GHRH mRNA expression and reduction of circulating IGF-I levels were observed in wild-type and Y4^–/– mice but not Y2^–/– or Y2^–/–Y4^–/– mice. In contrast, fasting-induced reduction of GnRH expression in the medial preoptic area and testis testosterone content were abolished in the absence of Y4 receptors. Colocalization of Y2 receptors and GHRH in the arcuate nucleus (Arc) suggests that GHRH mRNA expression in this region might be directly regulated by Y2 receptors. Indeed, hypothalamic-specific deletion of Y2 receptors in conditional knockout mice prevented the fasting-induced reduction in Arc GHRH mRNA expression. On the other hand, fasting-induced decrease in GnRH mRNA expression in the medial preoptic area is more likely indirectly influenced by Y4 receptors because no Y4 receptors could be detected on GnRH neurons in this region. Together these data show that fasting inhibits the somatotropic axis via direct action on Y2 receptors in the Arc and indirectly inhibits the gonadotropic axis via Y4 receptors.