Mechanism of Estrogen's Inhibitory Effects on Feeding

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DESCRIPTION (provided by applicant): The ovarian cycle has profound effects on food intake in a variety of species, including humans. This effect is very prominent in female rats which display a 20 - 40 percent decrease in food intake during the estrous (sexually receptive) phase of the cycle. This decline in food intake during estrus appears to be mediated, at least in part, by increased sensitivity to the satiety effects of cholecystokinin (CCK), a gut peptide that is released during meals and functions to decrease food intake by generating a satiety signal that is relayed to the brain via the vagus nerve. The importance of the rat's ovarian cycle in the control of food intake is revealed by ovariectomy, which increases food intake, decreases sensitivity to CCK, promotes body weight gain and, in the absence of estrogen replacement, induces obesity. Although the decline in estrogen activity appears to mediate the hyperphagia and associated body weight gain following ovariectomy, it is not known whether changes in endogenous estrogen activity mediate the decrease in food intake and increase in CCK satiation expressed during estrus in cycling rats. One goal of this proposal is to determine whether antagonism of central estrogen receptor activity will block the estrous-related decrease in food intake and increase in CCK satiation. To investigate this hypothesis, food intake and meal patterns will be monitored in cycling rats treated with an antiestrogen at various phases of the estrous cycle. A second goal is to use c-Fos immunocytochemistry, a marker of neuronal activity, to determine whether increased sensitivity to the satiety effects of CCK during estrus is mediated by increased responsivity of neurons that process satiety signals generated by consumption of a meal and by injection of CCK. A third goal of this proposal is to determine the brain areas where endogenous estrogen acts to decrease food intake and increase CCK satiation during estrus. In this experiment, in situ hybridization and immunocytochemistry techniques will be combined to determine whether those neurons that are activated by CCK express estrogen receptors. Together, these studies have the potential to broaden our understanding of the mechanism by which food intake is controlled across the estrous cycle of female rats. Because eating disorders are more prevalent in women than in men, this proposal targets an important research question with clear clinical relevance .