The role of AgRP neurons as a central link between leptin receptors and fertility

Leptin;Fertility;Gonadotropin;releasing;hormone;GnRH;AgRP;Agouti;Related;Peptide;Hypothalamus

Egan, Olivia Kate ; Anderson, Greg

University of Otago

关键词: Leptin;    Fertility;    Gonadotropin;    releasing;    hormone;    GnRH;    AgRP;    Agouti;    Related;    Peptide;    Hypothalamus;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/6714/1/EganOliviaK2016MSc.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Gonadotropin-releasing hormone (GnRH) neurons that reside in the hypothalamus are the central drivers of reproduction. GnRH stimulates the release of the gonadotropins luteinising hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary. The reproductive status of an individual is influenced by physiological and environmental modulation of the GnRH neuronal network. The processes involved in reproduction are energetically demanding so a strong relationship exists between metabolism and reproduction. Leptin is an adipocyte-derived hormone that plays a critical role in a number of physiological processes such as the control of energy balance and reproduction. Leptin circulates in the blood in proportion to the amount of white adipose tissue an individual has and can therefore directly communicate levels of energy reserves to the central nervous system (CNS). Humans and mice with deficient leptin signalling are obese and infertile due to lack of pubertal development and dysfunctional synthesis and secretion of LH, FSH and sex steroids.The neuronal pathways involved in the leptin-mediated control of reproductive function are not yet clearly defined. Previous research has indicated that GnRH neurons do not express leptin receptors (LepR) so leptin must exert effects through intermediate leptin-responsive neurons. Recent evidence has shown that leptin-signalling in neurons that produce gamma aminobutyric acid (GABA) is critical for reproductive function in mice but leptin signalling in glutamate neurons is not critical for normal puberty onset or fecundity. This narrows the pool of likely candidate populations involved in leptin-to-GnRH signalling to those that co-express GABA. Agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are an attractive candidate population as they express LepRs, are GABAergic and have previously been shown to modulate the activity of GnRH neurons. I aimed to investigate whether leptin actions on AgRP neurons are required and sufficient for puberty onset and subsequent fertility. Firstly, Cre-LoxP mice were used to target deletion of LepR to AgRP neurons. AgRP-LepR-knockout female mice exhibited a significant delay in the onset of estrous cycles compared to control animals. No significant differences in male puberty onset or adult fecundity in either sex were observed. Next, mice with a LoxP flanked transcription blocker sequence in the Lepr gene were crossed with AgRP-Cre mice to generate mice with AgRP neuron-specific rescue of LepR. LepR-null control females did not show any evidence of estrous cycles, while AgRP-LepR rescue females exhibited clear estrous cycles and subsequent fecundity that was not significantly different from LepR-intact controls. Puberty onset and fecundity were also rescued in AgRP-LepR rescue male mice when compared to LepR-null controls. These results indicate that leptin signalling in AgRP neurons is both required and sufficient for normal puberty onset in female mice, and is sufficient to maintain adult fecundity when leptin signalling is absent in all other cells.