Menopausal Sleep Fragmentation: Impact on Body Fat Gain Biomarkers in Women

项目总结 这个项目的主要目标是确定睡眠碎片化的影响 更年期睡眠障碍对女性体脂增加的影响。肥胖在中年人群中非常普遍， 老年女性，40岁后发病率显著增加，从而增加了患心血管疾病的可能性 绝经后的疾病、代谢综合征和糖尿病。在更年期过渡期间，超过50%的人 女性会增加身体脂肪，特别是腹部内脏脂肪组织，这与年龄增长无关。雌二醇 戒烟被认为是导致这些身体成分变化的原因。然而，停用雌二醇 不太可能完全解释这些变化，因为尽管普遍存在，但身体脂肪增加并不是一致的 进展为低雌激素血症，这是因为在绝经过渡期间，当 雌二醇仍然是间歇性产生的。几乎一半的女性在更年期过渡期间经历过这种情况， 与潮热有关的睡眠碎片可能会对这些身体成分的变化造成不利影响。在……里面 年龄较大的人，与年龄相关的总睡眠时间减少和睡眠碎片增加与 肥胖和不利的脂肪因子特征。在人类和动物模型中，实验性的睡眠限制和 碎片化导致与身体脂肪增加和肥胖有关的不利代谢生物标志物概况，包括 抑制瘦素，增加Ghrelin，降低脂联素，增加饥饿感和热量摄入量。 然而，以绝经过渡为特征的睡眠碎片化对体脂增加的影响及其 代谢生物标记物尚不清楚。虽然较低的雌二醇水平和潮热是睡眠的主要来源 在流行病学研究中，绝经中断与不利的脂肪因子谱有关，其作用 与更年期相关的高度普遍的睡眠障碍还没有得到调查。这项建议 会将一个实验性的睡眠碎片化范例与一个实验性的雌二醇戒断范例配对 在健康女性志愿者中模拟更年期以调查绝经相关睡眠的影响 体内脂肪增加的代谢和行为生物标记物的干扰。40名健康的绝经前妇女将 随机分配到住院患者的睡眠研究，包括3个不间断的夜晚，然后是3个试验性的夜晚 3个睡眠阶段的零碎夜晚，或相反的顺序：1)中晚期雌二醇值较高 卵泡期，2)雌二醇被促性腺激素释放激素激动剂和潮热抑制时 还没有开始，以及3)雌二醇抑制和潮热的出现。实验性的 设计将使睡眠碎片(目标1)、潮热(目标2)和雌二醇戒断的影响成为可能 (目标3)在这些生物标志物上相互分离。考虑到睡眠障碍在 更年期过渡，这一建议将为更年期相关睡眠的影响提供关键的见解 身体脂肪增加的标志物上的碎片化、潮热和激素变化，这将告知健康 预防中年女性体脂增加的促销策略。

PROJECT SUMMARY The broad goal of this project is to determine the impact of the sleep fragmentation that characterizes menopause-related sleep disturbance on body fat gain in women. Obesity is highly prevalent in midlife and older women, with rates accelerating markedly after age 40, thereby increasing the likelihood of cardiovascular disease, metabolic syndrome, and diabetes after menopause. During the menopause transition, over 50% of women gain body fat, specifically abdominal visceral adipose tissue, unrelated to chronological aging. Estradiol withdrawal is thought to be responsible for these body composition changes. However, withdrawal of estradiol is unlikely to exclusively explain these changes because body fat gains are not uniform despite universal progression to hypo-estrogenism and because body fat accrues during the menopause transition, when estradiol is still produced intermittently. Experienced by almost half of women during the menopause transition, sleep fragmentation related to hot flashes may contribute detrimentally to these body composition changes. In older individuals, age-related reduction in total sleep time and increase in sleep fragmentation are linked with obesity and an adverse adipokine profile. In human and animal models, experimental sleep restriction and fragmentation induce an adverse metabolic biomarker profile linked with body fat gain and obesity, including suppression of leptin, increase of ghrelin, decrease of adiponectin, and increased hunger and caloric intake. However, the impact of sleep fragmentation characterizing the menopause transition on body fat gain and its metabolic biomarkers is not known. While lower estradiol levels and hot flashes, the primary source of sleep disruption in menopause, have been linked with an adverse adipokine profile in epidemiologic studies, the role of the highly prevalent sleep disruption associated with menopause has not been investigated. This proposal will pair an experimental sleep fragmentation paradigm with an experimental estradiol withdrawal paradigm mimicking menopause in healthy female volunteers to investigate the impact of menopause-related sleep disruption on metabolic and behavioral biomarkers of body fat gain. Forty healthy premenopausal women will be randomly assigned to inpatient sleep studies involving 3 uninterrupted nights followed by 3 experimentally fragmented nights, or the reverse order, during 3 sleep periods: 1) when estradiol is high during the mid-to-late follicular phase, 2) when estradiol is suppressed by a gonadotropin-releasing hormone agonist and hot flashes have not begun, and 3) when estradiol is suppressed and hot flashes have developed. The experimental design will enable the impact of sleep fragmentation (Aim 1), hot flashes (Aim 2), and estradiol withdrawal (Aim 3) on these biomarkers to be isolated from each other. Given the prevalence of sleep disruption during the menopause transition, this proposal will provide pivotal insights into the impact of menopause-related sleep fragmentation, hot flashes, and hormone changes on markers of body fat gain, which will inform health promotion strategies to prevent gains in body fat in midlife women.