Date of Award

Spring 2020

Document Type

Open Access Dissertation

Department

Chemical Engineering

First Advisor

R. Michael Gower

Abstract

The adipose tissue functions as the body’s main energy reservoir and plays a central role in maintaining whole body energy homeostasis. The ability to modulate this tissue’s inherent endocrine and metabolic functions has promising implications in treating disease associated with adipose tissue dysfunction. This work revolves around two diseases where adipose tissue inflammation and metabolic dysfunction drive the disease, obesity and cachexia. Both diseases impact a significant population of U.S. adults and substantially reduce patient quality of life.

In this study, we first demonstrate the use of novel therapeutic platforms engineered to specifically target adipose tissue inflammation and lipid catabolism through localized drug delivery for the treatment of obesity. Specifically, we developed poly(lactide-coglycolide) scaffolds loaded with resveratrol, a small molecule with promising anti-obesity and anti-inflammatory properties, but one that suffers from poor bioavailability. Implant into the epididymal fat of lean mice indicates that resveratrol augments an antiinflammatory environment established by PLG scaffolds without drug. Furthermore, this strategy protected against inflammatory stimuli, such as mice fed a high fat diet and adipocytes treated with pro-inflammatory cytokines. Additionally, mice pre-treated with resveratrol loaded scaffolds and then fed a high fat diet gained significantly less body weight and adipose tissue mass compared to mice that received scaffolds without the drug. Collectively, this shows that PLG scaffolds are a promising platform for the treatment of metabolic diseases.

Secondly, we characterize the impact of chemotherapy treatment on adipose tissue remodeling as a model for cancer associated cachexia. Here we report for the first time that a clinically relevant bolus of doxorubicin significantly reduces animal body weight and induces fibrosis in subcutaneous adipose tissue in female rats. Similar to cachexic patients, this response was associated with an increase in collagen 1 and a marker of activated fibroblasts. Finally, we indicate that the subcutaneous adipose tissue exhibited greater fibrosis compared to visceral adipose tissue. This work is expected to provide greater understanding of doxorubicin’s potential role in promoting cancer-associated cachexia and provide insight for the development of future strategies to sustain adipose tissue health during chemotherapy treatment.

Rights

© 2020, Kendall Murphy

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