Graduation Year

2025

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Molecular Biosciences

Major Professor

Dominic D'Agostino, Ph.D.

Committee Member

Thomas Taylor-Clark, Ph.D.

Committee Member

Vrushank Davé, Ph.D.

Committee Member

Danielle Gulick, Ph.D.

Keywords

Metabolism, Ketones, Histone Modification, LPS-Induced Inflammation, Sex Effects, Olfaction-Based Learning, Splenomegaly

Abstract

Ketogenic diets are well-established therapeutic interventions for epilepsy, with documented neuroprotective effects arising from their metabolic, antioxidant and anti-inflammatory properties. Beyond epilepsy, ketogenic therapies are under investigation for various conditions including Alzheimer disease, cancer, diabetes, and cardiovascular disease. These diets suppress insulin levels and shift metabolic physiology toward fat and ketone body metabolism. This elevates circulating levels of ketone bodies, namely beta-hydroxybutyrate, acetoacetate, and acetone, which serve as both energy substrates and signaling molecules. The state of elevated ketone bodies (ketosis) can be achieved with various formulations of a ketogenic diet as well as exogenous ketone supplementation, though the signaling differences between these therapies are rarely addressed. In the following chapters we present an olfaction-based learning and memory protocol that can be used to study the behavioral sequelae of the neuroprotective effects of ketogenic diets; this protocol is robust against visual abnormalities and does not require motivational weight loss. Using this protocol, we demonstrate that pre-treatment with a ketogenic diet does not prevent LPS-induced weight loss or learning deficits in C57BL/6J mice, contrasting with protective effects observed in prior studies using exogenous ketone supplementation. However, we also present evidence that pre-treatment with a ketogenic diet is protective against LPS-induced splenomegaly and alters splenic macrophage nuclear post-translational modifications. These findings suggest that the anti-inflammatory effects of ketogenic therapies are likely dependent on the type of ketogenic therapy, are protective in organs outside of the brain, and that a ketogenic diet could be an effective immunomodulator. Further research needs to be done to understand how a ketogenic diet alters splenic macrophage activity. Sex effects of ketogenic therapies are also poorly understood in both basic research models and clinical applications. We present evidence that female and male VM/Dk mice have significant differences in body weight, circulating metabolites, blood insulin, and histone modification profiles. We also show that female and male mice respond differently to ketogenic therapies, and that the responses change depending on the type of ketogenic therapy. In conclusion, our results highlight the importance of considering sex as a biological variable in metabolic research and recognizing that the effects of ketogenic therapies differ across sexes and treatment strategies. These findings underscore the need for more nuanced research into the diverse mechanisms and outcomes of ketogenic therapies.

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