Mechanism of Estrogen's Inhibitory Effects on Feeding

描述（由申请人提供）：卵巢周期对包括人类在内的各种物种的食物摄入量具有深远的影响。这种影响在雌性大鼠中非常突出，在周期的发情期（性接受）阶段，雌性大鼠的食物摄入量减少了20 - 40%。发情期食物摄入量的下降似乎至少部分是由对胆囊收缩素（CCK）的饱腹感效应的敏感性增加介导的，胆囊收缩素是一种肠肽，其在进餐期间释放，并通过产生经由迷走神经传递到大脑的饱腹感信号来起到减少食物摄入的作用。大鼠卵巢周期在控制食物摄入中的重要性通过卵巢切除术揭示，卵巢切除术增加食物摄入，降低对CCK的敏感性，促进体重增加，并且在没有雌激素替代的情况下诱导肥胖。虽然雌激素活性的下降似乎介导卵巢切除术后的摄食过多和相关的体重增加，但尚不清楚内源性雌激素活性的变化是否介导了周期性大鼠发情期间食物摄入量的减少和CCK饱和度的增加。这项建议的一个目标是确定中枢雌激素受体活性的拮抗作用是否会阻断雌激素相关的食物摄入减少和CCK饱足增加。为了研究这一假设，将在发情周期的各个阶段监测用抗雌激素治疗的周期大鼠的食物摄入和膳食模式。第二个目标是使用c-Fos免疫细胞化学，神经元活动的标志物，以确定是否增加敏感性的饱腹感效应的CCK在发情期介导的增加的神经元的反应性，处理饱腹感信号产生的消费的一餐，并通过注射CCK。本研究的第三个目标是确定内源性雌激素在发情期减少食物摄入和增加CCK饱足的脑区。本实验将结合原位杂交和免疫细胞化学技术来检测CCK激活的神经元是否表达雌激素受体。总之，这些研究有可能扩大我们对雌性大鼠整个发情周期控制食物摄入的机制的理解。由于饮食失调在女性中比男性更普遍，因此该提案针对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 .