Skeletal Muscle Acetylation in Response to an Acute and Chronic High-Fat Diet
Kavanaugh, John Wesley
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The past thirty years have seen a dramatic rise in obesity worldwide owing to a change in dietary composition, quantity of food consumed- positive energy balance, and a more sedentary life style. Accompanied with obesity is a chronic low grade inflammatory state defined by increased circulating cytokines and an increase in gene expression promoting inflammation. Multiple health risks are associated with obesity such as cardiovascular disease, insulin resistance, and type II diabetes. Advances in mass spectrometry have made wide scale proteomic studies possible and are redefining cell and molecular biology. One such area of that has become of considerable interest is protein acetylation which is observed in most cellular processes such as cell cycle regulation, gene expression, subcellular localization, metabolism, muscle contraction, protein stability, apoptosis, and more. Metabolic proteins are highly susceptible to acetylation with almost all showing the capacity to be acetylated. Our research, using an obese mouse model fed a chronic high fat diet and a lean control mouse model fed a standard chow diet, showed numerous differences in the acetylome between obese and lean animals in a fasted state. As well as, differences in the acetylome's of both animal models upon receiving a high fat meal. We showed that almost every mitochondrially located metabolic protein in obese animals is hyper-acetylated in a fasted state compared to lean animals and that upon feeding lean animals have a greater response in the change to their metabolic acetylome. We show that in the fed state lean and obese mice have almost completely different acetylomic profiles of mitochondrial and glycolytic metabolic proteins. Furthermore, we have observed possible new regulatory mechanisms utilizing acetylation to 1) determine the fate of the co-factor NADH in glycolysis and 2) control an ATP producing reaction in glycolysis.
- Doctoral Dissertations