Conde, Kristine. The interaction of 17 beta-estradiol and GHSR expression in arcuate KNDy neurons and the impact on reproduction and energy balance in female mice. Retrieved from https://doi.org/doi:10.7282/t3-7pnd-0d91
DescriptionEstrogen signaling is a primary central regulator of reproduction and energy balance and ghrelin signaling is a critical modulator in the coordination between the two. In this dissertation, I elucidate the influence of E2 on GHSR signaling in KNDy neurons in the ARC of the hypothalamus and the critical yet understudied role it plays in modulating LH pulsatility, arcuate gene expression, the metabolic response to ovariectomy, diet-induced obesity, and the thermoregulatory response to cold stress. First, I characterized the 17β-estradiol (E2)-enhanced sensitivity to ghrelin in KNDy neurons utilizing Tac2-EGFP female mice. I discovered that KNDy neurons are indeed more sensitive to the inhibitory effect of ghrelin on the M-current, making these neurons more easily excitable. The next phase of investigation led to the development of a Kiss1-specific GHSR knockout mouse model utilizing Cre-lox technology. With this model, I further investigated the physiological importance of Ghsr expression in KNDy neurons and the regulation by E2. I found that deleting the GHSR in KNDy neurons alone is not sufficient to alter fertility, age of puberty or estrous cyclicity. Furthermore, I determined that KNDy regulation of LH pulsatility is strongly influenced by the interaction of E2 and Ghsr expression and exogenous ghrelin was able to significantly alter KNDy gene expression, revealing that reproduction and LH pulsatility are tightly regulated by an interaction of both ghrelin and E2. In addition, I found that our experimental (KNDy- GHSR KO) females treated with E2 had reduced metabolic rates. On a HFD, experimental females were resistant to diet-induced obesity exhibiting less adiposity and delayed glucose clearance. Finally, experimentals also respond to short-term cold stress overnight with increased activity and energy expenditure. In summary, my results indicate that there is a central pathway for the control of reproduction and metabolism coordination in female mice and it involves E2 and Ghsr expression ARC KNDy neurons.