Rapid Metabolic Control of the HPG System

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DESCRIPTION (provided by applicant): This multidisciplinary, international collaboration will broaden our understanding of infertility and related complications (e.g., osteoporosis) due to undernutrition, dieting, excessive exercise, anorexia nervosa, obesity and diabetes. The hypothalamic-pituitary-gonadal (HPG) system is dependent upon the availability of metabolic fuels, but the location and nature of the metabolic stimuli are unknown. Food restriction (FR) inhibits estrous cycles and pulsatile secretion of luteinizing hormone (LH), and these effects are reversed within hours after refeeding. FR leads to changes in a staggeringly long list of hormones, neuropeptides and metabolic events. The rapid effects of refeeding will allow us to pinpoint those neuroendocrine events that occur rapidly enough to account for the effects of refeeding, and to discount slower changes that serve functions other than reproduction. Radioimmunoassy, immunocytochemistry, in situ hybridization and pushpull perfusion will be used to measure circulating hormones (insulin, leptin, growth hormone, ghrelin) and brain neuropeptides (e.g., neuropeptide Y and corticotropin releasing hormone) in hamsters and sheep that have been either fed ad libitum, FR, or FR and then refed. In addition, FR hamsters and sheep will be refed with various macronutrients and fuels to determine the metabolic stimuli that are critical for rapid restoration of HPG function. The hamster's consistent, easily monitored four-day estrous cycle enables rapid progress in elucidating certain basic requirements for estrous cyclicity (Schneider laboratory, USA). The larger blood supply of the ewe will allow us to measure pulsatile LH secretion along with a wide array of other hormones and metabolic substrates in order to elucidate the acute events that underlie the initial stimulation of LH secretion (Clarke laboratory, Australia). Comparisons of species from two different taxa will test the generality of the conclusions.