The role of BRCA1 in regulation of lipid metabolism in skeletal muscle

说明(申请人提供)：更年期开始于生命的第五个十年，导致循环中的雌激素减少，这与内脏脂肪量的增加相一致，使妇女患代谢综合征的风险增加。随着妇女健康倡议的发布，医生们不得不重新考虑目前治疗绝经后妇女的选择。越来越重要的是要了解卵巢激素(即雌激素)丧失对妇女健康的生理后果，以便开发新的干预措施。我们的数据表明，去卵巢动物(OVX)表现出代谢综合征的症状，包括内脏脂肪增加，葡萄糖动力学受损和循环中脂质水平升高。我们认为OVX小鼠的这些变化是由于骨骼肌有效氧化脂质的能力降低所致，我们假设这部分是由乳腺癌早期发作1(BRCA1)基因介导的。这项研究将描述BRCA1在调节脂质进入骨骼肌线粒体中的作用，并试图确定BRCA1表达的减少是否有助于OVX模型中腹型肥胖的增加。 公共卫生相关性：更年期或手术摘除卵巢后循环雌激素浓度大幅下降会导致内脏肥胖症增加。由于雌激素治疗不被认为是一个可行的选择，这项建议将寻求了解骨骼肌在较长时间内暴露于低水平雌激素时的变化。在这里，我们设计了一项深入的探索性研究，将解决绝经后妇女调节脂质利用的细胞机制的失调问题。

DESCRIPTION (provided by applicant): Menopause begins in the fifth decade of life and results in decreased circulating estrogens which coincides with increases in visceral fat mass placing women at elevated risk for the developing the metabolic syndrome. With the release of the Women's Health Initiative doctors have to reconsider current options for treating postmenopausal women. It is increasingly important to understand the physiological consequences of the loss of ovarian hormones (i.e. estrogens) on women's health so new interventions can be developed. Our data indicate that ovariectomized animals (OVX) exhibit symptoms of the metabolic syndrome, including increased visceral fat, impaired glucose dynamics and high circulating levels of lipid. We believe these changes in the OVX mice are due to a reduced ability of the skeletal muscle to effectively oxidize lipid, which we hypothesize is mediated in part by the gene breast cancer early onset 1 (BRCA1). This study will delineate the role of BRCA1 in regulating lipid entry into the mitochondria of skeletal muscle and attempt to determine if decreases in BRCA1 expression contribute to increased abdominal obesity in the OVX model. PUBLIC HEALTH RELEVANCE: Large decreases in circulating estrogen concentration either via menopause or surgical ovariectomy results in increased visceral adiposity. Since estrogen therapy is not considered a viable option, this proposal will seek to understand how skeletal muscle changes when exposed low levels of estrogens over an extended period of time. Here, we have designed an in-depth exploratory study that will address the dysregulation of cellular mechanisms that regulate lipid utilization in post-menopausal women.