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. / Ph. D. / In recent decades obesity rates have been on the rise because of a change in diet that is high in fat and sugar. Associated with obesity are increased risks of cardiovascular disease, insulin resistance, and type II diabetes. Obesity is also known to promote the expression of genes responsible for a low grade inflammatory state.
Utilizing mass spectrometry, it is now possible to measure the addition or removal of modifying groups, termed posttranslational modifications (PTMs), to proteins tissue wide. Acetylation is one such PTM whose addition or removal can both promote or inhibit protein activity. Posttranslational modifications are one way of regulating metabolism by altering the ability to oxidize fats, carbohydrates, or proteins. The modifying group for acetylation, acetyl CoA, is also the product of carbohydrate, fat, and amino acid metabolism making acetylation an integral regulator of metabolism.
Our research measured the changes in acetylation to metabolic proteins between lean and obese mouse models as well as the effect of a single high fat meal on acetylation changes in lean and obese models. We showed hyper-acetylation due to obesity inhibits changes in acetylation of metabolic proteins unlike lean animals which show a greater number of acetylation changes in response to fasting and feeding.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/81138 |
| Date | 11 December 2017 |
| Creators | Kavanaugh, John Wesley |
| Contributors | Human Nutrition, Foods and Exercise, Hulver, Matthew W., Li, Liwu, Frisard, Madlyn I., Schmelz, Eva M. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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