Date of Award

2024

Embargo Period

4-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Neurology

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Catrina Sims-Robinson

Second Advisor

Adviye Ergul

Third Advisor

Andreana Benitez

Fourth Advisor

Jeffrey Jones

Fifth Advisor

Jim Oates

Abstract

Obesity afflicts nearly half of the adult population in the United States and is strongly associated with age-related dementia. Hyperinsulinemia-induced insulin resistance is a common comorbidity amongst obese individuals and is linked to both poor cerebral perfusion and brain insulin deficiency. Insulin plays vital roles in the regulation of blood flow and various cognitive processes, including memory. As such, poor insulin action within and transport across the cerebrovasculature may predispose obese individuals to cognitive impairment. The central hypothesis of this dissertation was devised following an extensive literature review (Chapter 1) and asserts that obesity-associated hyperinsulinemia impairs insulin receptor endocytosis into the cerebrovascular endothelium, thereby preventing the propagation of insulin signaling cascades, reducing blood flow to the brain, and promoting cognitive decline.

To test our hypothesis, we devised a multifaceted approach that assessed both physiologic function and biologic mechanisms (Chapter 2). We assessed metrics of cognition and cerebrovascular function in a preclinical murine model of diet-induced obesity, where we discovered that high-fat feeding influenced spatial working memory and damaged cerebrovascular structure and function (Chapter 3). Diet-induced obesity further hindered insulin receptor transport within the brain microvasculature, a finding which was replicated in hyperinsulinemic brain endothelial cell cultures (Chapter 4). The observed failure of insulin receptor endocytosis into hyperinsulinemic brain endothelial cells (Chapter 4) occurred alongside aberrant phosphorylation of key internalization- and insulin signaling-effectors (Chapter 5). A downstream impairment in insulin-mediated vasodilatory capacity was further observed in hyperinsulinemic endothelial cells (Chapter 5), highlighting the functional consequences of hyperinsulinemia-induced insulin resistance on cerebrovascular function.

As discussed collectively in Chapter 6, we conclude that diet-induced obesity and hyperinsulinemia impair signaling through and internalization of the insulin receptor, an event which holds significant implications for cerebral perfusion, brain insulin availability, and cognitive performance.

Rights

Copyright is held by the author. All rights reserved.

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