Mechanism of Estrogen's Inhibitory Effects on Feeding

描述(申请人提供)：卵巢周期对包括人类在内的各种物种的食物摄入量有深远的影响。这种影响在雌性大鼠身上表现得非常明显，在发情(性接受)阶段，雌性大鼠的摄食量减少了20%-40%。发情期间摄食量的下降似乎至少部分是由于对CCK饱腹感的敏感性增加，CCK是一种在进餐时释放的肠肽，通过产生饱腹感信号，通过迷走神经传递到大脑，从而减少摄食量。卵巢切除揭示了大鼠卵巢周期在控制食物摄入量方面的重要性，卵巢切除增加了食物摄入量，降低了对CCK的敏感性，促进了体重增加，在没有雌激素替代的情况下，会导致肥胖。虽然雌激素活性的下降似乎介导了卵巢切除后的过度吞噬和相关的体重增加，但尚不清楚内源性雌激素活性的变化是否介导了动情大鼠发情期间摄食量的减少和CCK饱满度的增加。这项建议的目的之一是确定中枢雌激素受体活性的拮抗是否会阻止与动情有关的食物摄入量的减少和CCK饱足感的增加。为了研究这一假说，将监测在发情周期的不同阶段用抗雌激素治疗的周期大鼠的食物摄入量和进食模式。第二个目标是使用c-Fos免疫细胞化学，神经元活动的标记物，来确定在发情期对CCK饱腹感效应的敏感性增加是否是通过处理由进食和注射CCK产生的饱腹感信号的神经元的反应性增加所介导的。这项建议的第三个目标是确定发情期间内源性雌激素作用于减少食物摄入量和增加CCK饱足感的大脑区域。在这项实验中，将结合原位杂交和免疫细胞化学技术来确定那些被CCK激活的神经元是否表达雌激素受体。总而言之，这些研究有可能拓宽我们对雌性大鼠发情周期中食物摄入量控制机制的理解。由于进食障碍在女性中比在男性中更普遍，这项建议针对的是一个具有明确临床相关性的重要研究问题。

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 .