In female mammals, reproduction is extremely sensitive to the availability of oxidizable metabolic fuels. When food intake is limited or when an inordinate fraction of the available energy is diverted to other uses such as exercise or fattening, reproductive attempts are suspended in favor of processes necessary for individual survival. Both reproductive physiology and sexual behaviors are influenced by metabolic fuel availability. Nutritional effects on reproductive physiology are mediated by changes in the activity of gonadotropin-releasing hormone (GnRH) neurons in the forebrain, whereas the suppression of sexual behaviors appears to be due, at least in part, to decreases in estrogen receptors in the ventromedial hypothalamus. Work using pharmacological inhibitors of glucose and fatty acid oxidation indicates that reproductive physiology and behavior respond to short-term (minute-to-minute or hour-to-hour) changes in metabolic fuel oxidation, rather than to any aspect of body size or composition (e.g., body fat content or fat-to-lean ratio). These metabolic cues seem to be detected in the viscera (most likely in the liver) and in the caudal hindbrain (probably in the area postrema). This metabolic information is then transmitted to the GnRH-secreting or estradiol-binding effector neurons in the forebrain. This metabolic fuels hypothesis is consistent with a large body of evidence and seems to account for the infertility that is seen in a number of situations, including famine, eating disorders, excessive exercise, cold exposure, lactation, some types of obesity, and poorly controlled diabetes mellitus. The experiments proposed in this application focus on the physiological processes mediating deficits in female sexual behavior that are seen in nutritional infertility. One group of proposed experiments is directed at determining how information about metabolic fuel availability is transmitted from the putative detectors to forebrain effector cells, including the neural pathways and neurotransmitters involved. Another group of experiments addresses the potential role of the adipose tissue hormone, leptin, in the behavioral aspects of nutritional infertility. A third proposed line of research examines the effects of altered partitioning of metabolic fuels on estrous behavior and neural steroid receptors. The fourth group of experiments assesses the effects of energetic challenges on preoptic area steroid receptors and positive feedback effects of estradiol and progesterone on LH release.
