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。绝经前女性心脏代谢疾病的发病率低于年龄匹配的男性。绝经后，当循环雌激素下降时，女性患代谢综合征和心脏病的风险急剧增加。昼夜节律系统也是新陈代谢和肥胖的关键调节器。昼夜节律是由位于身体几乎每个组织中的分子钟网络产生的行为和生理的24小时周期。这些生物钟受到食物和光线等线索的影响，通常与环境的明暗周期同步。对轮班工作者的研究表明，昼夜节律系统的破坏会增加肥胖、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调节代谢的雌激素相关昼夜节律机制，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。迄今为止，大多数研究都调查了男性肥胖和糖尿病的昼夜节律调节。雄性小鼠的高脂肪饮食喂养严重扰乱了日常节律，这种昼夜节律的破坏调节了饮食诱导的肥胖。相比之下，对女性的昼夜节律和新陈代谢之间的相互作用知之甚少。本研究的目的是探讨雌激素信号传导、限时喂养和昼夜节律在调节小鼠和女性肥胖及其合并症中的相互作用。我们将检验中心假设，即每日代谢节律受雌激素信号调节，是治疗绝经后妇女肥胖和糖尿病前期的治疗靶点。在目标1中，实验将阐明雌二醇保护雌性小鼠的日常代谢节律免受高脂喂养破坏的分子机制。这些机制将研究使用全球雌激素受体（ER）基因敲除小鼠和靶向ER在肝细胞中的表达。然后，我们将确定时间限制喂养是否抑制雌性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受不良。在目标2中，实验将检验时间限制喂养改善绝经后妇女代谢危险因素的假设。使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配到16周的时间限制喂养干预或无干预对照组，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，胰岛素敏感性和体重的变化作为主要结果。总之，这些实验将阐明雌激素，每日节律和干预措施，目标昼夜节律，以减轻代谢功能障碍之间的相互作用。

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.