Circadian regulation of metabolic risk in mice and women: role of estrogen and time-restricted feeding

Project: Research project

Project Details

Description

Obesity is a deadly and very costly disease in the United States because it substantially increases the risk for heart disease, stroke, many cancers, and type 2 diabetes (T2D), which together account for 50% of all deaths1-5. Men and women differ in their susceptibility to obesity-related disorders. Young, premenopausal women have a lower incidence of cardiometabolic disease compared to age-matched men6,7. Estrogen is a primary protective factor impacting this sex-difference. After menopause, when circulating estrogens decline, a womans risk for metabolic syndrome (MetS) and heart disease increases by 60%8-10. When women take estrogen shortly after menopause onset, the risk of T2D and heart disease is lower compared to postmenopausal women without estrogen treatment11,12. Although estrogens have complex functions, they generally protect women from cardiometabolic dysfunction.
The circadian system is also a critical player in the regulation of metabolism and obesity13. 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 environmental 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, MetS, and T2D14-18. Our overall objectives are to elucidate the circadian mechanisms that regulate metabolism and to test interventions that target the circadian system and are effective in humans.
Most studies to date have investigated circadian regulation of obesity and diabetes in males19-23. We and others have shown that high-fat diet feeding in male mice profoundly disrupts daily rhythms (e.g. food intake rhythm, physical activity) and that this circadian disruption causes diet-induced obesity19,20,24,25. 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. Our proposed studies are strongly supported by preliminary data showing that: 1) daily rhythms of eating behavior and locomotor activity, as well as circadian timekeeping in the liver, are not disrupted by high-fat diet feeding in female mice that are also resistant to diet-induced obesity26; 2) daily metabolic rhythms are profoundly disrupted after removal of circulating estrogens by ovariectomy in females26; 3) estradiol treatment of ovariectomized females restores protection of daily metabolic rhythms during high-fat feeding; 4) Post-menopausal women, who have very low estrogens, have disrupted daily rhythms of eating, and this disruption is associated with metabolic risk27,28; 5) restoring the daily rhythm of eating to ovariectomized female mice (a preclinical model of post-menopausal women) using time-restricted feeding, inhibits diet-induced obesity, insulin resistance, and glucose intolerance29.
Based on these data, we will test the central hypothesis that daily metabolic rhythms are regulated by estrogen signaling and are therapeutic targets to treat obesity and pre-diabetes in post-menopausal women. We will investigate the estrogen signaling mechanisms that regulate daily rhythms underlying diet-induced obesity in mice. Because the routine use of estrogens in women is impractical, we will determine if a time-restricted feeding intervention will improve insulin sensitivity in metabolically-unhealthy post-menopausal women under free-living conditions.
Aim 1: To elucidate the molecular mechanisms by which estradiol protects daily metabolic rhythms from disruption by high-fat feeding in mice. We will investigate the molecular estrogen signaling mechanisms that regulate eating and locomotor activity rhythms and the phase of the liver circadian clock in mice. We will study these me
StatusActive
Effective start/end date4/1/211/31/26

Funding

  • HHS: National Institutes of Health (NIH): $205,813.00

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