Author ORCID Identifier

http://orcid.org/0000-0002-2444-6491

Year of Publication

2016

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Pharmacology and Nutritional Sciences

First Advisor

Dr. Shuxia Wang

Abstract

Obesity and its associated comorbidities are of global concern. These complications are largely driven by perturbations in energy homeostasis, inflammation, and oxidative stress within metabolic tissues. Although these underlying pathways have been established, molecular mechanisms augmenting metabolic dysfunction have not been fully defined. CD47, a ubiquitously expressed cell membrane receptor, has been previously implicated in the development of inflammation and oxidative stress in a number of disease conditions. Previous work from our lab and others has confirmed that the most potent ligand of CD47, TSP1, plays a critical role in facilitating inflammation and metabolic dysfunction in diet-induced obesity. Whether these effects of TSP1 are mediated by CD47 has never been explored. Specifically, the functions of CD47 in white and brown adipose tissue, skeletal muscle, and the liver have never been characterized under obese conditions. Within our studies, we clearly defined distinct regulatory functions of CD47 in different metabolic tissues of a diet-induced obesity rodent model. We found that CD47 deficiency was associated with reduced adiposity and systemic inflammatory markers which preserved glucose homeostasis. In white adipose tissue, CD47 deficiency was associated with suppressed inflammation and macrophage recruitment which may be attributed to smaller adipocyte size driven by enhanced lipid mobilization. Further, whole body CD47 deficiency stimulated brown adipose tissue energy expenditure through increased FFA-mediated uncoupling and enhanced fatty acid oxidation. Interestingly, no significant changes were observed in skeletal muscle-dependent energy expenditure. In the liver, both TSP1 and CD47 deficiency protected mice from diet-induced fatty liver disease. In vitro studies demonstrated that TSP1 induces liver oxidative stress comparable to free fatty acids and that CD47 blockade partially attenuates this effect. From these studies, we concluded that increased lipid turnover fueled the enhanced energy requirements of activated brown adipose tissue resulting in a leaner phenotype despite high fat diet challenge. In addition, the increased TSP1-CD47 protein expression in the liver may augment ROS in fatty liver disease. Together, these studies provide evidence to suggest CD47 may contribute to metabolic dysfunction in a tissue-specific manner and that the pathological roles of CD47 function should expand to include obesity and its associated comorbidities.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2016.491

Available for download on Thursday, December 13, 2018

Share

COinS