Obesity, Leptin Resistance and Ovarian Function in Mice

小鼠肥胖、瘦素抵抗和卵巢功能

基本信息

批准号：
6664711
负责人：
MAUREEN R DIGGINS
金额：
$ 12.25万
依托单位：
AUGUSTANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-07 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Infertility and other reproductive disorders are among the many health-related consequences of obesity. Circulating concentrations of leptin, a hormone secreted by fat cells, become greatly elevated in obesity and can lead to the development of leptin resistance. In addition to its role in regulating metabolism and appetite, leptin participates in control of reproduction. Gonadotropic control of the ovaries is dependent upon leptin modulation in the hypothalamus, and evidence suggests that leptin plays a significant role in the direct regulation of ovarian function. Hyperleptinemia has been correlated with impaired reproductive function. Nevertheless, leptin appears to exert generally positive effects on ovarian function under experimental conditions. A possible explanation for this paradox, which has not been investigated, is that the association between high leptin levels and diminished reproductive function is due to leptin resistance. The proposed research will test the novel hypothesis that a state of leptin resistance in ovarian target cells contributes to diminished fertility in obesity. Two specific aims will be addressed, (1) to determine whether adult onset obesity in mice leads to ovarian leptin resistance and (2) to determine the relationship between ovarian leptin resistance and follicular dynamics and oocyte developmental competence. Mice possessing a specific deletion in the promoter region of the agouti protein gene, i.e. lethal yellow mice (C57BL/6J-Ay/a), develop adult-onset obesity, progressive loss of fertility, elevated circulating leptin levels, and hypothalamic leptin resistance. Specific markers of ovarian leptin resistance and measurements of ovarian function will be compared between Ay/a mice and same strain non-mutant black (C57BL/6J a/a) mice at three distinct ages, 100, 150, and 200 days. To dissociate central from ovarian effects, endogenous gonadotropin secretion will be suppressed by treatment with GnRH antagonist. Ovaries will be stimulated with equine chorionic gonadotropin (eCG) and ovulation induced with human chorionic gonadotropin (hCG). The overall objective of the proposed research is to answer the novel question of whether leptin resistance is manifested in the ovary, and if it is related to impaired ovarian function. The results will hopefully provide a strong foundation for future studies to elucidate the precise role of leptin and leptin resistance in ovarian function and fertility.

描述（由申请人提供）：不孕症和其他生殖障碍是肥胖带来的许多与健康相关的后果之一。瘦素（一种由脂肪细胞分泌的激素）的循环浓度在肥胖症中大大升高，并可能导致瘦素抵抗的发展。除了调节新陈代谢和食欲外，瘦素还参与控制生殖。卵巢的促性腺控制依赖于下丘脑中瘦素的调节，有证据表明瘦素在卵巢功能的直接调节中发挥着重要作用。高瘦素血症与生殖功能受损有关。然而，在实验条件下，瘦素似乎对卵巢功能产生总体积极的影响。对这一悖论的一个可能解释（尚未得到研究）是，高瘦素水平与生殖功能减弱之间的关联是由于瘦素抵抗。拟议的研究将测试一个新的假设，即卵巢靶细胞的瘦素抵抗状态会导致肥胖者的生育能力下降。将解决两个具体目标：（1）确定小鼠成年发病肥胖是否导致卵巢瘦素抵抗；（2）确定卵巢瘦素抵抗与卵泡动力学和卵母细胞发育能力之间的关系。刺鼠蛋白基因启动子区域具有特定缺失的小鼠，即致命性黄色小鼠（C57BL/6J-Ay/a），会出现成年肥胖、逐渐丧失生育能力、循环瘦素水平升高和下丘脑瘦素抵抗。将在三个不同年龄（100、150 和 200 天）的 Ay/a 小鼠和同种非突变黑色 (C57BL/6J a/a) 小鼠之间比较卵巢瘦素抵抗的特定标志物和卵巢功能的测量结果。为了将中枢作用与卵巢作用分开，内源性促性腺激素分泌将通过 GnRH 拮抗剂治疗来抑制。将用马绒毛膜促性腺激素 (eCG) 刺激卵巢，并用人绒毛膜促性腺激素 (hCG) 诱导排卵。拟议研究的总体目标是回答瘦素抵抗是否在卵巢中表现出来以及是否与卵巢功能受损有关的新问题。这些结果有望为未来的研究提供坚实的基础，以阐明瘦素和瘦素抵抗在卵巢功能和生育能力中的确切作用。