The central theme of this application for an NIMH Senior Scientist Award is the reciprocal interactions between metabolic fuels and reproduction. 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 receptor 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 ration). 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. There is no evidence to date for direct detection of metabolic cues by these forebrain effector neurons. This metabolic fuels hypothesis is consistent with a large body of evidence and seems to account for the fertility 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 will test a number of the predictions of a metabolic fuels hypothesis of nutritional infertility. During naturally occurring changes in reproductive status (puberty, pregnancy, ovulatory cycles), fluctuations in the circulating ovarian steroids (estradiol and progesterone) have striking effects on the behavioral and physiological controls of energy balance. A second aspect of this research program investigates the physiological mechanisms by which ovarian steroids affect regulatory behaviors and energy metabolism.
