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

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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.