Project Summary: Reproduction is energetically demanding and as a result, the hypothalamic-pituitary-gonadal (HPG) axis is tightly regulated by metabolic factors. However, the specific neural circuitry underlying the interaction between metabolic and reproductive state remains incompletely understood. The melanocortin-3 receptor (MC3R) plays a critical role in the bi-directional communication between metabolic state and reproductive function, and the utility of the MC3R to address reproductive disorders is untested. The MC3R is ideally positioned both anatomically and functionally, to mediate direct communication between metabolic state and the reproductive axis. MC3R is expressed in nearly 100% of the AgRP neurons, the primary neurons of the central melanocortin system, as well as in secondary target sites of the melanocortin system, such as the kisspeptin neurons. Furthermore, female mice lacking MC3R exhibit altered reproductive cycle lengths and do not suppress reproductive cycles in response to fasting. Both mice and humans with MC3R mutations show delays in pubertal onset, demonstrating the highly conserved role of this receptor. Our preliminary data show that male MC3RKO mice are significantly delayed in pubertal onset, whereas female MC3RKO mice have a delay to first estrus. Hypothalamic MC3R expression follows a sexually dimorphic pattern in both mice and humans, however sex differences in MC3R control of reproductive function have not been explored. For example, little is known about the role of this receptor in the physiology and pathophysiology of HPG axis control. In this application, I will study the neuroendocrine role of MC3R in the physiology and pathophysiology of HPG axis control. The principal investigator in this training grant, Dr. Danielle Porter, has extensive experience in reproductive neuroendocrinology and neuroanatomy. In this training grant, Dr. Porter will receive additional training in metabolic physiology and pharmacology from the primary research mentor, Dr. Roger Cone. Furthermore, under the guidance of an expert team of collaborators, Dr. Porter will receive hands on training in whole brain imaging and further training in neuroendocrinology. Together, the mentorship and training in this K99/R00 application will provide the necessary technical and conceptual background for Dr. Porter to initiate an independent research program focusing on MC3R neural circuits as therapeutic targets for disorders at the interface of reproduction and metabolism.