All ETDs from UAB

Advisory Committee Chair

Sumanth D Prabhu

Advisory Committee Members

Martin E Young

James F George

Anath Shalev

Louis Dell'Italia

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Obesity is a state of chronic low-grade systemic inflammation that, along with type 2 diabetes (T2D), increases the risk of developing cardiovascular disease (CVD). Despite the wealth of information on the link between macrophages and cytokines in adipose tissue and peripheral insulin resistance, their role in the pathogenesis of diabetic cardiomyopathy and cardiac diastolic dysfunction is unclear. We hypothesized that activated immune cell mediators, in particular monocytes and macrophages, are fundamental drivers of diet-induced obesity and diabetic cardiomyopathy. Herein, firstly, a diet-induced model of diabetic cardiomyopathy was developed in C57BL/6 mice by feeding a high fat diet (HFD, 45% kcal fat) for 6 months, using 10% kcal fat as a control diet (CD,). Secondly, using this model, we established the inflammatory cell profile, including monocytes and macrophages, in the systemic circulation, adipose tissue, heart, and spleen during the progression of obesity, T2D and diabetic cardiomyopathy. Thirdly, the role of monocytes and macrophages in the development and progression of type 2 diabetes associated cardiomyopathy was demonstrated by their reversible and selective ablation using Macrophage Fas-Induced Apoptosis causative role in the development of diet-induced obesity/T2D and diabetic cardiomyopathy, and comprise potential immunomodulatory targets for the development of new therapies aimed at alleviating T2D, diabetic cardiomyopathy, and diastolic dysfunction.

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