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Title: Kisspeptin stimulates growth hormone release by utilizing Neuropeptide Y pathways and is dependent on the presence of ghrelin

item FORADORI, C - Auburn University
item WHITLOCK, B - Auburn University
item DANIEL, J - Berry College
item ZIMMERMAN, A - Auburn University
item JONES, M - Auburn University
item READ, C - Auburn University
item SMITH, J - Auburn University
item CLARKE, I - Monash University
item Elsasser, Theodore
item SARTIN, J - Auburn University

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/13/2017
Publication Date: N/A
Citation: N/A

Interpretive Summary: In terms of growth and development, one of the major hormones that regulates growth and metabolism is growth hormone. For decades it was thought that the regulation of the reproductive axis, however, occurred independent of the endocrine system components, like growth hormone, that regulate growth. Recently, new discoveries have uncovered some strong links between the growth and reproductive axes that suggest that some common linkages that are found in some proteins that regulate each hormone axis may be essential to the proper timing of events in development of animals that makes growth more efficient. Researchers at Auburn University, Monasche University in Australia and the USDA investigated some of the mechanisms through which this fine tuning of the link between the growth and reproductive processes occurs. In the regulatory region of the brain called the hypothalamus, a small protein hormone called kisspeptin plays a large role in regulating the synthesis and release of reproductive hormones. Our collective work now shows that some specific features of kisspeptin are critical for the regulation of growth hormone secretion under some very specific metabolic stated. Kisspeptin specifically was shown to be a major regulator of metabolism and nutrient processing for growth under states of altered/reduced food intake. This signaling is important because in times of low nutrient availability, the animal's focus needs to shift from reproductive processes to the metabolic processes, largely catabolic in terms of fat mobilization, that can maintain homeostatic control of protein synthesis. Our research was successful in mapping some pathways through which this is accomplished; data such as this can may be useful to animal management scenarios that involve better understanding of metabolic processes in times of nutrient stress and undernutrition.

Technical Abstract: Although kisspeptin is the primary stimulator of gonadotropin releasing hormone secretion and therefore the hypothalamic-pituitary gonadal axis, new findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Central delivery of kisspeptin caused a robust rise in plasma GH in short-term fasted but not fed sheep. Kisspeptin induced GH was no different in animals fasted for 24 hours than those fasted for 72 hours, suggesting that the factors involved in the kisspeptin induced GH are responsive to loss of food availability and not due to negative energy balance. Pretreatment with the selective neuropeptide Y (NPY) Y1 receptor antagonist, BIBO3304, blocked the effects of kisspeptin induced GH release, implicating NPY as an intermediary and further implicating the need for short-term fasting. Dual-immunofluorescence demonstrated that kisspeptin treatment in fasted animals resulted in increased c-FOS immunoreactivity, a marker of cellular activation, in NPY and growth hormone releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-FOS in somatostatin (SS) immunoreactive cells of the periventricular nucleus of the hypothalamus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor removed or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and arcuate NPY expression rise which permits kisspeptin activation of NPY cells subsequently stimulating GHRH cells and inhibiting SS cells resulting in GH release. In presenting our findings, we postulate that kisspeptin may convey reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.