Regulation of luteinizing hormone release by neuropeptide Y: Diverse actions enhancing steroid feedback

This dissertation examines a key player in the central control of reproduction, namely neuropeptide Y (NPY). NPY acts at both the hypothalamus and pituitary to augment gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion. These actions are extremely dependent on the presence of estrogen (E₂); when E₂ levels are low, NPY instead suppresses LH release. In addition to its reproductive effects, NPY has been found to exert a powerful influence on body weight. The dual role of NPY in reproduction and metabolism has led to speculation that NPY acts as the elusive “bridge molecule” that shuts down reproduction when the body's energy reserves run low. These studies use NPY-deficient mice (NPYKO) and in vitro techniques to examine the mechanisms by which NPY influences LH release and how steroid hormones and metabolic stimuli modulate its actions.; Our results reveal that NPYKO mice exhibit a substantial and specific deficit in the amplitude of preovulatory LH surges that partially results from the absence of NPY's actions on the anterior pituitary. These findings demonstrate unequivocally that secretion of normally proportioned LH surges depends on the actions of NPY. Furthermore, these results suggest that by priming the mouse anterior pituitary gland for the LH surge, NPY is partly responsible for the dramatic increase in pituitary sensitivity to GnRH on proestrus that is crucial for successful ovulation. We also obtain striking evidence that in the presence of E₂, NPY acts through gonadotroph NPY Y1 receptor (Y1R) to augment LH release; pharmacological blockade of the receptor curtails NPY's actions in primary gonadotrophs. These findings suggest that E₂ prepares the hypothalamic-pituitary axis on multiple levels for the actions of NPY, leading to a robust LH surge necessary for reproduction. Finally, we find that NPY is required for the suppression of basal LH release that normally accompanies food deprivation in female mice. These actions, too, are E₂ dependent. These studies establish the crucial role NPY plays in augmenting the LH surge, reinforcing the actions of E₂, and integrating the neuronal control of reproduction and energy homeostasis.