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Gonadotropin-Releasing Hormone-Expressing Neurons Immortalized Conditionally Are Activated by Insulin: Implication of the Mitogen-Activated Protein Kinase Pathway

Service of Endocrinology, Diabetology, and Metabolism (R.S., E.C., M.-J.V., M.G., J.-P.R., R.C.G., F.P.P.) and Service of Internal Medicine (P.V.), Department of Medicine, University Hospital, 1011 Lausanne, Switzerland; and Service of Endocrinology (F.P.P.), Diabetology and Metabolism, University Hospital, 1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Francois P. Pralong, M.D., Service of Endocrinology, BH 19-709, University Hospital, 1011 Lausanne, Switzerland. E-mail: francois.pralong{at}chuv.ch.

Energy balance exerts a critical influence on reproduction via changes in the circulating levels of hormones such as insulin. This modulation of the neuroendocrine reproductive axis ultimately involves variations in the activity of hypothalamic neurons expressing GnRH. Here we studied the effects of insulin in primary hypothalamic cell cultures as well as a GnRH neuronal cell line that we generated by conditional immortalization of adult hypothalamic neurons. These cells, which represent the first successful conditional immortalization of GnRH neurons, retain many of their mature phenotypic characteristics. In addition, we show that they express the insulin receptor. Consistently, their stimulation with insulin activates both the phosphatidylinositol 3-kinase and the Erk1/2 MAPK signaling pathways and stimulates a rapid increase in the expression of c-fos, demonstrating their responsiveness to this hormone. Further work performed in parallel in immortalized GnRH-expressing cells and primary neuronal cultures containing non-GnRH-expressing neurons shows that insulin induces the expression of GnRH in both models. In primary cultures, inhibition of the Erk1/2 pathway abolishes the stimulation of GnRH expression by insulin, whereas blockade of the phosphatidylinositol 3-kinase pathway has no effect. In conclusion, these data strongly suggest that GnRH neurons are directly sensitive to insulin and implicate for the first time the MAPK Erk1/2 signaling pathway in the central effects of insulin on the neuroendocrine reproductive axis.

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