Leptin and NPY regulation of GnRH secretion and energy homeostasis

Evidence from our laboratory demonstrated that NPY-producing neurons in the ARC regulate both reproduction and energy homeostasis. The mechanisms by which NPY participates in these two instinctual drives are being delineated. Although normally NPY stimulates GnRH secretion and appetite, energy deficit upregulates NPYergic signaling to sustain a robust appetitive drive and to shut down reproduction. Neural links of NPY neurons with other peptidergic systems and coproduced peptides, such as AgRP and GABA, are commandeered to turn on appetite and turn off reproduction. Since estrogen and leptin receptors are expressed on ARC NPY neurons, it is likely that these peripheral signals directly regulate NPYergic signals. Seemingly, caloric deficit, produced by undernourishment or fasting, downregulates leptin resulting in increased NPYergic signaling and consequently attenuation of GnRH secretion. Conversely, downregulation of NPYergic signaling by cytokines, such as CNTF and leptin, normalizes GnRH secretion even in energy-deficit animals. We have found a regional heterogeneity in the function of ARC NPY neurons. Whereas gene expression in the entire population of ARC NPY neurons was turned on by caloric and leptin deficit, only a subpopulation of neurons in the middle-caudal region of the ARC was turned on by the ovarian steroid treatment that readily evokes a GnRH surge. Our ongoing studies are designed to delineate the molecular events underlying the rapid "on" and "off" influence of NPY neurons on appetitive and reproductive processes.