Kisspeptin and the neuroendocrine control of reproduction

Dr Smith’s work represents an exciting new field of neuroendocrinology. The recent discovery of mice and humans lacking the kisspeptin receptor and their infertile phenotype has sparked scientists to explore the actions of this novel neuropeptide. The activity of kisspeptin neurons is now known to be absolutely vital for fertility in both females and males. Dr Smith’s research hopes to provide significant advancement to our knowledge of kisspeptin, how it works and defining its critical role in stimulating GnRH release and fertility.

Are the effects of stress on the reproductive system mediated by kisspeptin signalling?

It is well known that stress has an inhibitory effect on fertility. Increased plasma concentrations of cortisol (in response to stress) inhibit normal reproductive function by suppressing gonadotrophin secretion, but the mechanisms involved are largely unknown. This project aims to determine whether the neuropeptide kisspeptin plays a role in mediating the effects of stress on the reproductive system. The project will involve measurement of Kiss1 mRNA (the kisspeptin gene) in the brains of animals subjected to acute psychosocial stress. Furthermore, the response to kisspeptin treatment will also be determined in stressed animals. Techniques will include collection of blood samples with subsequent analysis by LH radio-immunoassay. Collection of brain tissues will also be performed for subsequent in situ hybridization and immunocytochemistry analysis.

The role of kisspeptin in the placenta:

In humans, kisspeptin secretion into the peripheral circulation increases dramatically (approximately ten thousand-fold) during pregnancy and declines precipitously at term, indicating a placental origin. Moreover, plasma kisspeptin is elevated in gestational trophoblastic neoplasia but Kiss1 mRNA expression is reduced in term pre-eclampsia placentas, indicating a role for kisspeptin as a physiological trophoblast invasion inhibitor. Dr Smith aims to determine the expression of Kiss1 mRNA in the mouse placenta and examine the effect of gestational age and feto-placental growth restriction.

The effect of kisspeptin on energy expenditure:

Recent data from our laboratory demonstrate no effect of central kisspeptin treatment on accumulative food intake. Despite this, kisspeptin results in the activation of NPY cells in the hypothalamus. Electrophysiological data also suggests kisspeptin regulates the activity of NPY, and also POMC neurons. Taken together, these data strongly suggest kisspeptin has effects on energy expenditure. Experiments will be conducted to measure the direct effect of kisspeptin and kisspeptin antagonist on energy expenditure. Calorimetry experiments in mice will also be conducted. Finally, if kisspeptin effects on NPY and/or POMC neurons were direct, kisspeptin receptor expression must be expressed in these neurons. Double label in situ hybridization experiments will be conducted to determine this. Results from these experiments will shed light on the known link between the reproductive system and metabolism and will, potentially, offer novel therapeutic alternatives for the treatment of obesity and related metabolic disorders.

Collaborator/s

  • Dr Alexander Kauffman, University of California