Date of Award

2019

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Jung Han Kim, Committee Chairperson

Second Advisor

Dr. Eric Blough

Third Advisor

Dr. Elsa Mangiarua

Fourth Advisor

Dr. Travis Salisbury

Fifth Advisor

Dr. Nalini Santanam

Abstract

Obesity is a global epidemic, affecting all ages. It is one of the leading causes of preventable death, as it increases the risk of type 2 diabetes (T2D), hypertension, cardiovascular disease, nonalcoholic fatty liver disease, and some cancers. Obesity is a complex disease that is caused by a combination of genetic and environmental factors such as diets high in fat and sedentary life style. Despite our increased knowledge of obesity development and progression, current obesity treatments have not stopped the rise in obesity rates. There are still many unknowns related to the underlying mechanisms of obesity that need to be investigated and understood, so that treatment of obesity can be more effective. To deal with the numerous variables involved with such studies, animal models are recommended. My dissertation centers around characterizing the TALLYHO/Jng (TH) mouse, a polygenic model for T2D and obesity, and identifying obesity gene(s) in this model. The first study focused on investigating the effect of diets high in fat and sucrose for the development of obesity and T2D in TH mice. Compared to normal C57BL/6J (B6) mice, TH mice responded more sensitively to the obesogenic diets in the development of obesity and type 2 diabetes, demonstrating that diets are important modulators of genetic susceptibility to the diseases in this model. The second study was conducted in an effort to identify obesity gene(s) in TH mice. We generated congenic mouse strains carrying obesity quantitative trait loci on chromosome 1 derived from TH mice on B6 background. Using these mouse strains, we determined that the distal segment of chromosome 1 from TH mice is necessary to cause diet induced obesity. In the last study, we demonstrated that increased pro-inflammatory cytokine interleukin-6 levels and decreased mitochondrial respiration may be in part a mechanism underlying the gene-diet interaction in advancing obesity and type 2 diabetes in TH mice.

Subject(s)

Obesity -- Research.

Obesity -- Complications -- Research.

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