Modulating macrophage phenotype for obesity therapy

Obesity increases the risk of conditions such as cardiovascular disease, type 2 diabetes, and certain types of cancer. This is believed to be due to a chronic state of inflammation deriving from excess nutrients in visceral adipose tissue which surrounds the internal organs. Macrophage cells are key mediators in this inflammation through crosstalk with adipocytes in adipose tissue. However, it is apparent that macrophages are also involved in beneficial metabolic processes like maintaining energy balance and directing lipid metabolism. Current therapies aim to address health issues arising from obesity by suppressing appetite or decreasing nutrient absorption which can lead to a host of gastrointestinal side effects, nutrient insufficiency, and decrease in muscle weight and bone density over time. Anti-inflammatory pharmaceutical drugs can theoretically address the chronic inflammation originating from adipose tissue, but these drugs have significant off target effects, like gastrointestinal distress and liver toxicity, which limit their potential for long-term use. Off-target effects occur because the targets of these drugs exist in diverse cell types throughout the body. For this reason, there is a need to deliver these drugs solely to macrophages in adipose tissue. The Smith Lab at Illinois has shown dextran nanocarriers to be effective carriers for the delivery of anti-inflammatory drugs to adipose tissue. However, it is unclear which types of anti-inflammatory pharmaceutical drugs are most effective for modulating adipose tissue macrophages and how carrier properties such as size affect therapeutic efficacy. Here, I show a dextran-drug nanocarrier capable of delivering an anti-inflammatory drug to adipose tissue for obesity therapy to modulate both inflammatory and metabolic biology of adipose tissue macrophages. I first identify gene expression signatures of inflammatory and metabolically activated macrophages and discuss potential drug modulators of these phenotypes. Next, I investigate uptake mechanisms of dextran in inflammatory macrophages in vitro and adipose tissue depots in vivo. I determine that dextran nanocarriers of higher molecular weights (≥ 70 kDa) are well posed for specific targeting to obese adipose tissue. Additionally, using a dextran-based nanocarrier formulation of an anti-inflammatory drug, I report weight loss that is not associated with changes in appetite in mice fed a high-fat diet and establish that this treatment is also associated with metabolic activation in adipose tissue. Lastly, I propose a synergistic drug combination based on a glucocorticoid receptor agonist and histone demethylase inhibitor. This combination works to both lower inflammatory gene expression and suppress expression of genes supporting macrophage metabolic dysfunction. I expect that this work could lead to the development of a dextran-drug nanocarrier that is translational, exhibits favorable targeting to adipose tissue, and is conjugated to a drug pair that will work together to synergistically improve metabolic activation and suppress inflammation in adipose tissue macrophages.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Gonzalez Medina, Natalia Yaratzeth

Contributors dc:contributor

• Smith, Andrew M
• Nie, Shuming
• Nelson, Erik R
• Sirk, Shannon

• drug delivery
• nanocarrier
• inflammation
• macrophage

Statement dc:rights

• Copyright 2025 Natalia Gonzalez Medina

Language dc:language

en

Handle dc:identifier

https://hdl.handle.net/2142/132487

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132487