Date of Award

8-7-2026

Embargo Period

8-7-2028

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Pathology

College

College of Graduate Studies

First Advisor

Jeffrey Jones

Second Advisor

Adviye Ergul

Third Advisor

Amy Engevik

Fourth Advisor

Hongkuan Fan

Fifth Advisor

Catrina Sims-Robinson

Sixth Advisor

Andy Shih

Abstract

Obesity is a major public health concern and a significant risk factor for cognitive decline and dementia, particularly when present during midlife. While the link between obesity and impaired brain health is well established, the factors that determine how metabolic dysfunction affects cerebrovascular function and cognition remain incompletely understood. In particular, the roles of diet onset, duration of exposure, and sex in shaping these outcomes have not been systematically examined. The central hypothesis of this dissertation is that diet-induced obesity drives time- and sex-dependent alterations in cerebral perfusion and vascular architecture that impair cognitive function.

To test this hypothesis, a multifaceted approach was employed, combining in vivo and in vitro analyses. Using a preclinical mouse model of diet-induced obesity, we first assessed the effects of adolescent- and adult-onset high-fat diet exposure on cerebral perfusion and vascular architecture. We then evaluated the behavioral and metabolic consequences of adult-onset obesity, focusing on recognition memory and spatial working memory. Finally, we examined transcriptomic and cellular responses to obesity-associated hyperinsulinemia in key components of the blood–brain barrier, including endothelial cells and pericytes.

Our findings demonstrate that early-life exposure to a high-fat diet produces the most pronounced brain region-specific hypoperfusion and alterations in vascular architecture, with distinct sex-specific patterns. These changes were accompanied by sex-specific impairments in cognitive performance in adulthood and midlife, with females exhibiting greater susceptibility to deficits in recognition memory. In parallel, hyperinsulinemic conditions induced distinct transcriptomic changes in vascular-associated cells, indicating cell-specific responses at the blood–brain barrier.

Collectively, this work highlights the importance of diet timing, duration, and sex in determining the impact of obesity on cerebrovascular and cognitive outcomes. These findings provide new insight into early changes associated with obesity and identify vascular and cellular alterations that may contribute to later-life cognitive decline.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Monday, August 07, 2028

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