Bridging the neuroendocrine control centers; Fertility and Nutrition. Identifying the role that POMC-derived peptides play in the neuroendocrine control of fertility.

Abstract

Reproductive activity and metabolic function are two separate neuroendocrine controlled processes. There is a degree of overlapping hormonal and neuronal regulatory mechanisms. The functional activity of the former is mediated by the HPG axis. GnRH neurons located at the top of the axis regulate the secretion of LH and FSH. These are the primary gonadotropic hormones that act peripherally to convey central instructions to the gonads. Through the HPG axis, the fertility of the animal is primarily regulated. Other inputs, such as those from the metabolic centers of the brain can interfere with fecundity and pubertal onset. The aim of the following thesis was to investigate how necessary MC4R’s on GnRH neurons are in allowing fertility in mice. POMC derived signaling peptides involved in metabolic modulation act centrally via MC4R. The Cre-LoxP re-expression technique was used to re-introduce MC4R signalling in GnRH neurons following a brain wide knockout. Two experimental approaches were undertaken to assess the effects of MC4R ablation and restoration; 1. Fecundity and pubertal onset were monitored in an extended male fertility study 2. LH ELISA was undertaken to mark the effect of MT-II, an agonist of the MC4R, in the null versus restored MC4R mice. Three experimental groups were included in the study; wildtype controls, MC4R-null (with global knockout of the MC4R) and MC4R-GnRH rescue (restoration of MC4R functioning only in GnRH neurons). Due to the importance of the MC4R in weight regulation, subjects of the latter two groups increased significantly in weight following pubertal onset that itself of which, was not significantly different from the wildtype animals. The weight increase, rather than a direct effect of MC4R ablation on GnRH neurons was probably the limiting factor for allowing fecundity. The second experiment did not move beyond a pilot study. A range of doses of MT-II was injected both centrally and peripherally. Even at the highest dose, which fell way beyond recommendations by previous papers, an LH response could not be induced. The current experiment was plagued by small experimental group sizes due to breeding difficulties and minimal statistical significance, although a provisional conclusion was drawn; the POMC/MC4R system may play a relatively minor role with regards to interactions between hypothalamic nuclei that mediate the interface of neuronal control of fertility and nutrition. This is in accordance with the idea of evolutionary redundancy in multiple neuronal pathways that are regulating fertility and therefore survival of the species. The signaling pathway of POMC derived peptides via the MC4R on GnRH neurons should be considered sufficient rather than necessary in the neuroendocrine control of fertility.