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. ? ?
| Xiao, Ennian; Kim, Andrea J; Dutia, Roxanne et al. (2010) Effects of estradiol on cerebrospinal fluid levels of agouti-related protein in ovariectomized rhesus monkeys. Endocrinology 151:1002-9 |
| Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2008) Astressin B, a nonselective corticotropin-releasing hormone receptor antagonist, prevents the inhibitory effect of ghrelin on luteinizing hormone pulse frequency in the ovariectomized rhesus monkey. Endocrinology 149:869-74 |
| Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2005) Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology 146:784-9 |
| Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2004) Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 89:5718-23 |
