AbstractsBiology & Animal Science

Identification and Characterization of Leptin Responsive Neurons Involved in the Metabolic Control of Reproduction

by Wieteke Ameliek Zuure

Institution: University of Otago
Year: 0
Keywords: Leptin; Reproduction; Hypothalamus; GnRH
Record ID: 1315236
Full text PDF: http://hdl.handle.net/10523/5487


Reproductive function is an adaptive system that is critical for the survival of all species. In vertebrates, fertility (the ability to reproduce) is regulated by the hypothalamic-pituitary-gonadal (HPG) axis. This axis is centrally driven by the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. There are many endogenous and exogenous factors that can influence the HPG axis; here I focus on metabolic regulation of fertility. The adipokine leptin, primarily produced by adipose tissue, circulates throughout the body in concentrations relative to the amount of energy stored in the adipose tissue. Leptin plays a critical role in the hypothalamic control of energy balance, but also has profound effects on central regulation of reproduction. The effect of leptin on the HPG axis is indirect, as GnRH neurons do not express leptin receptor (Quennell et al., 2009). Therefore it is assumed that intermediate leptin responsive neurons must exist that provides leptin-to-GnRH signaling. Trying to elucidate this neuronal pathway has been a challenge to many researchers in the field over the past years, as Lepr neurons exhibit a widespread and heterogynous distribution throughout the brain. Here, I investigated different neuronal pathways and neurotransmitters that might relay the signal of leptin onto the HPG axis. I used transgenic mouse models to visualize Lepr neurons, and combined that with retrograde tract tracing to identify leptin responsive inputs to the region of GnRH neurons. Additionally, conditional deletion of the receptors for leptin from neuronal nitric oxide synthase (nNOS), glutamate, and γ-aminobutyric acid (GABA) neuron populations was used to assess the effects on reproductive function. With these experiments I investigated the role of these neurons and signaling molecules in mediating leptin-to-GnRH signaling. From these studies I found that Lepr neurons, particularly from the arcuate nucleus of the hypothalamus (Arc), provide neuronal input to the region of the GnRH neurons. Recent literature shows that leptin signaling in nNOS neurons might play a role in the metabolic regulation of fertility, however my attempt to conditionally delete Lepr from nNOS neurons was unsuccessful, presumably due to an incompatibility of the Cre and LoxP genes used. I found that leptin signaling in glutamate neurons is not critical for reproductive functioning. Most interestingly I found that GABA neuron specific Lepr knockout caused significant disruptions in reproductive functioning. Both females and males displayed delayed puberty onset. Observations of various adult fertility parameters revealed that these knockout animals have decreased fecundity and females had disordered estrous cycles. These experiments showed that leptin signaling in GABAergic neurons plays a critical role in the metabolic regulation of fertility. These exciting results were followed up by measuring changes in hypothalamic gene expression between control and GABA specific Lepr knockout females. The GABA specific Lepr knockout females…