Author ORCID Identifier

https://orcid.org/0000-0001-8899-756X

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Biology

First Advisor

Dr. Julie S. Pendergast

Abstract

Circadian rhythms are approximately 24-hour cycles of behavior, physiology, and gene expression. In mammals, these circadian rhythms are generated by clocks located in nearly every tissue in the body. The function of circadian clocks is to synchronize physiology and behavior with environmental cycles such as the light-dark cycle. After menopause, when circulating levels of estrogens are very low, women are more susceptible to obesity comorbidities such as metabolic syndrome and cardiovascular disease, suggesting that estrogens regulate these processes. Estrogens could protect females from metabolic dysfunction by regulating circadian rhythms. Consumption of diets that are high in fat contribute to obesity. Consumption of high-fat diet (HFD) disrupts daily rhythms in male mice and they develop diet-induced obesity (DIO). In contrast, previous studies have shown that female C57BL/6J mice are resistant to HFD-induced obesity. Daily rhythms in female C57BL/6J mice are also resistant to disruption by HFD feeding. Female mice maintain robust daily rhythms of eating behavior and locomotor activity during HFD feeding. The circadian organization of molecular rhythms in tissues in female mice are also protected from HFD-induced disruption. When circulating estrogens are removed by ovariectomy (OVX), females are susceptible to DIO when fed HFD, just like male mice. HFD feeding also disrupts daily rhythms in OVX females. The goal of this dissertation was to investigate the role of estrogens in protecting daily rhythms in female mice from disruption by HFD feeding. We found that estradiol replacement to physiological levels in OVX females restored high-amplitude eating behavior and activity rhythms during HFD feeding so they resembled intact females. Time-restricted feeding of OVX females at the proper time of the day (12-hour active phase) inhibited obesity and improved glucose tolerance and insulin sensitivity. We next investigated the mechanism by which estradiol signaling mediates its protective effect against disruption of daily metabolic rhythms in female mice. We measured the effects of HFD feeding on daily rhythms in global estrogen receptor α knockout (ERα KO) female mice. We found that ERα was necessary to protect daily eating behavior and locomotor activity rhythms from disruption by HFD feeding. The phases of circadian clocks in tissues were also altered in ERα KO mice. The phases of PER2::LUC rhythms in the SCN and liver were advanced in both male and female ERαKO mice compared to ERα WT mice fed low-fat diet. HFD feeding exacerbated the phase advance of the live circadian clock in female ERα KO mice, but not in ERα WT mice. Taken together these results shows that estrogen signaling via the ERα receptor inhibits diet-induced obesity in part by regulating daily metabolic rhythms.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.331

Funding Information

This research was funded by National Institutes of Health grants R03DK107851, K01DK098321, P30GM127211, P30DK020579, P30DK058404, and UL1TR001998, as well as the Gertrude F. Ribble Grant, and the University of Kentucky.

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