Dr. Chua has recently embarked upon a project to understand the impact of leptin signaling on the reproductive system, principally the GnRH neurons. While it is known that leptin signaling deficiency causes hypothalamic hypogonadism and infertility, GnRH neurons do not express leptin receptors, indicating that leptin must act indirectly. Dr. Chua has combined several different genetic manipulations with leptin receptor deficiency that restores pubertal development along with reproductive and lactational competency to obese leptin receptor-null female mice. Specifically, manipulations of melanocortinergic transmission is sufficient to restore pubertal development and reproductive function in leptin receptor deficient females.
Past work has shown that some models of leptin signaling deficiency have restored reproduction, such as ob/ob Y5r-null and ob/ob Npy-null models. However, most of these models do not show restored mammary gland development with the dams being unable to lactate. Thus, there is clear evidence that mammary gland development is regulated separately from the ovaries and the endometrium. Dr. Chua’s project is aimed at understanding the integrated neurohumoral mechanisms that permit coordinated development of the entire reproductive axis. Further work is being done to understand the neural circuits involved in regulating reproduction.