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. Nalini Santanam, Committee Chairperson

Second Advisor

Dr. Elsa Mangiarua

Third Advisor

Dr. Jung Han Kim

Fourth Advisor

Dr. Shekher Mohan

Fifth Advisor

Dr. Regina Lamendella

Abstract

Oxidative stress plays a key role in metabolic syndrome which includes obesity and cardiometabolic diseases. It is implicated that oxygen-derived free radicals generated during the mitochondrial electron transport chain alter the function of specific biological components, thus activating obesogenic pathways such as glucose and lipid signaling. Research on this topic is of vital importance as obesity is a high-risk factor in the development and progression of severe, debilitating, life-threatening maladies such as cardiometabolic diseases, chronic inflammatory pathologies, and cancer. Furthermore, there is no universal effective therapy to combat the rising rates of obesity with over 1.9 billion (39%) adults classified as obese worldwide. Catalase is an antioxidant enzyme that helps to catabolize hydrogen peroxide and has been shown in vivo and/or in vitro to decrease oxidative stress in vascular cells, skeletal muscle tissue, and adipose tissue which results in mitigating free radical damage in the heart, aging-effects in muscle tissue, insulin resistance as well as dysfunctional glucose signaling, and cancer progression. With redox stress being one of the major hallmarks of obesity, we hypothesized that overexpression of antioxidant catalase would suppress redox stress-mediated obesogenic pathways. In our studies, we first generated and investigated the effect of excess endogenous antioxidant by using a novel mouse model termed “Bob-Cat.” These mice are a cross between heterozygous, leptin-deficient mice (Ob/+) and [Tg(CAT)± ] mice that ubiquitously express human catalase in addition to mouse catalase. We first showed sex specific changes in redox stress, phenotype, metabolic parameters, and adipose tissue function. These findings indicated this ‘stress-less’ model (overexpressing antioxidant) would be optimal to study in combination with frequently prescribed diet and exercise intervention strategies to alter key biomarkers related to obesogenic pathways. In an 8 week feeding study, we showed ad libitum feeding of an enriched omega 3 diet, in contrast to a high saturated fatty acid/ polyunsaturated fatty acid diet, promoted maintenance of body weight and fat mass, increased energy metabolism, normal circadian rhythm, and insulin sensitivity within the novel mice. These findings were evidenced to be a result of up-regulation of GPR120- Nrf2 cross-talk (>30 fold, p<0.05), which to our knowledge, had not been previously evidenced in any other studies. We also showed the role of sexual dimorphism in response to OM3 rich diet. In relation to exercise, we showed evidence that antioxidant overexpression in addition to moderate treadmill exercise 30 min. a day, 5 days/week for 8 weeks resulted in maintenance or lowered body weight and fat mass, balanced energy metabolism, a normal feeding circadian rhythm, and improvement in the lipid profile. Most interestingly, we saw significant differences in skeletal muscle Type 1 / Type 2 fiber ratio and mRNA expression of key myokines which may have induced a change in adipose tissue-brain cross-talk. Additionally, this study provided evidence of an exercise and redox-induced shift in the taxa and predicted function of the gut microbiome which beneficially impacted energy metabolism in the mice overexpressing antioxidant catalase. Taken together, our studies suggest antioxidant overexpression is an efficient adjuvant to diet and exercise intervention to combat metabolic dysfunction. Therefore, the newly generated Bob-Cat mouse is an effective model to investigate redox stress in the context of energy metabolism, metabolic tissue dysfunction, and the gut microbiome to discover new preventative treatments and therapies to reduce the rising levels of obesity, cardiometabolic diseases, chronic inflammatory – related illnesses, and cancer.

Subject(s)

Free radicals (Chemistry) -- Physiological effect.

Superoxide -- Physiological effect.

Antioxidants.

Metabolic syndrome.

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