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Author ORCID Identifier

https://orcid.org/0000-0002-5791-301

Date Available

5-1-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Biology

Faculty

Julie Pendergast

Faculty

Jakub Famulski

Abstract

Circadian rhythms are approximately 24-hour cycles of physiology and behavior. Circadian rhythms of eating, or meal timing, are linked to cardiometabolic dysfunction in humans. Mistimed eating, such as breakfast skipping and eating late at night, increases the risk of obesity, diabetes, and cardiovascular disease in humans. Likewise, disrupted eating rhythms cause obesity in mice. This dissertation investigates how estrogens regulate eating behavior rhythms and tissue clock timing in female mice. Chapter 1 reviews three key components critical to this work. The first is an overview of the field of chronobiology and the function of the circadian system. The second is the synthesis, signaling, and expression of estrogens and its receptors. The third is estrogen regulation of the circadian system. Prior research found a sex difference in eating behavior rhythm amplitude in mice during high-fat feeding, where male mice had blunted eating rhythm amplitudes, but female mice did not. This protection of the eating rhythm amplitude during high-fat feeding was attributed to estrogens in female mice. However, it was not known whether estrous cycles regulated eating rhythms. In Chapter 2, I found that endogenous, cycling ovarian hormones regulated the amplitude of the eating rhythm in female mice, whereby higher amplitude eating rhythms coincided with elevated estrogen signaling. Thus, female mice had more consolidated feeding behavior during high estrogen signaling stages compared to low estrogen signaling stages. Next, I investigated the estrogen signaling mechanism that regulated eating behavior rhythms in females fed high-fat diet. In Chapter 3, I found that an estrogen receptor alpha (ERα) agonist, propyl pyrazole trisphenol (PPT), enhanced the amplitude of the eating rhythm in female mice. The amplitude of the eating rhythm was more than two-fold greater with PPT treatment compared to vehicle. Lastly, prior research found that the timing, or phases, of peripheral circadian clocks, such as the liver, entrain to meal timing. Since I found that an ERα agonist enhanced the amplitude of the eating rhythm in female mice, I next investigated whether the phase of the liver and other circadian clocks were affected by ERα signaling. In Chapter 4, I measured circadian organization, which is the stable phase relationship between central and peripheral clocks, in female mice with altered ERα signaling. I found that global ERα knockout mice had advanced liver clock phases compared to wild-type females. Further, treatment of ovariectomized female mice with systemic PPT restored the phase of the liver clock to that of a gonadally intact female. These data showed that liver clock phase is regulated by ERα in female mice. Together, these data suggest a potential mechanism by which ERα regulates cardiometabolic health in female mice. These studies expand our knowledge of estrogens as biological modifiers of circadian rhythms in female mice.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.222

Archival?

Archival

Funding Information

These studies were funded by the University of Kentucky Center for Clinical and Translational Science TL1 fellowship (2024; TL1TR001997), the Biology department Merit and Morgan fellowships, and the Biology department Gertrude F. Ribble pilot funds received by Victoria Alvord (2021, 2022, 2024, 2025). These studies were also supported by grants awarded to Dr. Julie Pendergast from the National Institute of Health (R01DK124774) and National Science Foundation (IOS-2045267) both awarded in 2021.

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