Circadian Regulation of Metabolic Risk in Mice and Women: Role of Estrogen and Time-Restricted Feeding

摘要文本 项目摘要 男性和女性对肥胖相关疾病的易感性不同，雌激素是女性的主要保护因素。与年龄匹配的男性相比，绝经前女性心脏代谢性疾病的发病率较低。绝经后，当循环中的雌激素下降时，女性患新陈代谢综合征和心脏病的风险会急剧增加。昼夜节律系统也是新陈代谢和肥胖的关键调节因素。昼夜节律是大约24小时的行为和生理循环，由位于身体几乎每一个组织中的分子时钟网络产生。这些时钟受食物和光线等信号的影响，通常与环境的明暗周期同步。对倒班工人的研究表明，昼夜节律系统的紊乱会增加肥胖、心脏病、代谢综合征和2型糖尿病的风险。我们的总体目标是阐明与雌激素相关的调节新陈代谢的昼夜节律机制，并测试针对昼夜节律系统的干预措施，使雌激素缺乏的妇女受益。到目前为止，大多数研究都调查了男性肥胖和糖尿病的昼夜节律。雄性小鼠的高脂肪饮食严重扰乱了日常节律，这种昼夜节律的紊乱调节了饮食诱导的肥胖。相比之下，人们对女性昼夜节律和新陈代谢之间的相互作用知之甚少。这项建议的目的是研究雌激素信号、限时进食和昼夜节律之间的相互作用，以调节小鼠和女性的肥胖及其共病。我们将验证这一中心假设，即每日代谢节律受雌激素信号调节，是治疗绝经后女性肥胖和糖尿病前期的靶点。在目标1中，实验将阐明雌二醇保护雌性小鼠日常代谢节律免受高脂饮食干扰的分子机制。这些机制将使用全局雌激素受体(ER)基因敲除小鼠并通过靶向肝细胞中的ER表达来研究。然后，我们将确定限时喂养是否能抑制雌性ER基因敲除小鼠的饮食诱导的肥胖、胰岛素抵抗和葡萄糖耐量异常。在目标2中，实验将检验限制时间喂养改善绝经后妇女代谢风险因素的假设。采用双臂随机对照临床试验设计，代谢不健康的绝经后妇女将被随机分为16周限时喂养干预组和无干预对照组，我们将通过活动记录仪测量代谢和人体测量结果以及昼夜休息-活动模式，主要结果是胰岛素敏感性和体重的变化。总之，这些实验将阐明雌激素、日常节律和针对昼夜节律的干预措施之间的相互作用，以缓解代谢功能障碍。

Abstract Text Project Summary Men and women differ in their susceptibility to obesity-related disorders and estrogen is a primary protective factor in women. Premenopausal women have a lower incidence of cardiometabolic disease compared to age- matched men. After menopause, when circulating estrogens decline, a woman’s risk for metabolic syndrome and heart disease increases dramatically. The circadian system is also a critical regulator of metabolism and obesity. Circadian rhythms are ~24-hour cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. These clocks are entrained by cues such as food and light and are typically synchronized with environmental light-dark cycles. Studies of shift workers, who have disordered exposure to food and light, show that disruption of the circadian system increases risk of obesity, heart disease, metabolic syndrome, and type 2 diabetes. Our overall objectives are to elucidate the estrogen-related circadian mechanisms that regulate metabolism and to test interventions that target the circadian system and benefit women who are estrogen deficient. Most studies to date have investigated circadian regulation of obesity and diabetes in males. High-fat diet feeding in male mice profoundly disrupts daily rhythms and this circadian disruption regulates diet-induced obesity. In contrast, very little is known about the interplay between circadian rhythms and metabolism in females. The objective of this proposal is to investigate the interaction between estrogen signaling, time-restricted feeding, and circadian rhythms in regulating obesity and its comorbidities in mice and women. We will test the central hypothesis that daily metabolic rhythms are regulated by estrogen signaling and are therapeutic targets to treat obesity and prediabetes in postmenopausal women. In Aim 1, experiments will elucidate the molecular mechanisms by which estradiol protects daily metabolic rhythms from disruption by high-fat feeding in female mice. These mechanisms will be studied using global estrogen receptor (ER) knockout mice and by targeting ER expression in hepatocytes. Then we will determine whether time-restricted feeding inhibits diet-induced obesity, insulin resistance, and glucose intolerance in female ER knockout mice. In Aim 2, experiments will test the hypothesis that time-restricted feeding improves metabolic risk factors in postmenopausal women. Using a two-arm randomized controlled clinical trial design, metabolically-unhealthy postmenopausal women will be randomized to either a 16-week time-restricted feeding intervention or no intervention control and we will measure metabolic and anthropometric outcomes and circadian rest-activity patterns by actigraphy, with change in insulin sensitivity and body weight as primary outcomes. Together, these experiments will elucidate the interplay between estrogens, daily rhythms, and interventions that target circadian rhythms to alleviate metabolic dysfunction.