Energy-Related Peptides and Reproductive Axis

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DESCRIPTION (provided by applicant): Nutritional deprivation is associated with reproductive dysfunction and can lead to functional hypothalamic chronic an ovulation (FHCA). Even though this is a frequent cause of infertility, the exact metabolic clues that signal the brain remain to be determined. Our main objective is to investigate whether recently discovered energy-related peptides, such as the peripherally-secreted ghrelin and the centrally-secreted agouti-related peptide (AGRP), may function as clues that modulate the gonadotropin-releasing hormone (GnRH) pulse generator, the pacemaker for the hypothalamic-pituitary-gonadal (HPG) axis. Since these peptides are orexigenic and are upregulated during fasting, our central research hypothesis is that administration of these peptides in a normal animal will mimic the under-fed state and result in the inhibition of the GnRH pulse generator. Aims 1 and 2 will investigate whether AGRP or ghrelin infusion can inhibit pulsatile LH release, a reflection of GnRH pulse activity. Because AGRP is co-located with neuropeptide Y (NPY) in arcuate neurons, we will also investigate synergy between these 2 peptides. Since both AGRP and ghrelin activate the hypothalamic-pituitary-adrenal (HPA) axis, additional protocols will document the role of functional central pathways, including that of HPA, in mediating the action of these energy-related peptides on the GnRH pulse generator. In aims 3 and 4, we will extend our studies to the role of energy-related peptides in 2 physiopathological models which modify GnRH/LH pulsatility, one evoking food restriction, the other a psychogenic stress, and investigate whether direct or indirect antagonism of energy-related peptides or an infusion of leptin, an anorexigenic peptide, can restore normal pulsatile activity. Our studies will be performed in the rhesus monkey, a non-human primate which mimics well the physiology and physiopathology of the human reproductive system. Overall, our data will provide novel information in support of a role of new orexigenic peptides in nutrition-related and perhaps also psychogenic stress-related reproductive dysfunction and infertility.