Recent studies have show a decrease in oxidative capacity is associated with obesity, insulin resistance, hypertension and in some individuals, the development of type 2 diabetes. Indeed, oxidative capacity is an excellent predictor of life expectancy. Decreases in skeletal muscle mitochondrial oxidative phosphorylation can be found in individuals who are prone to the development of type 2 diabetes. While these alterations can be found in relatively young individuals at high risk for diabetes, it is not clear whether this alteration is due to an inherent defect in skeletal muscle oxidative capacity or is due to acquired changes. In addition, it remains to be determined whether interventions at an early age can alter the metabolic profile of those at risk for type 2 diabetes. An outbred, genetically heterogeneous colony of rats with inherited differences in oxidative capacity base on low (LCR) and high (HCR) running capacity show differences in the propensity to develop a phenotype consistent with the 'metabolic syndrome'. The LCR colony has many of the same alteration in mitochondrial-related function as has been described in humans and thus provides a model to investigate the molecular causes and treatment of the metabolic syndrome. Interestingly, the HCR colony was found to have gene expression profiles suggesting that they perceive a caloric restriction, despite an increase in food intake. The studies will use a systems approach, combining metabolomics, gene expression and bioinformatics to define the underlying molecular changes in metabolism that lead to alterations in oxidative capacity.
In Specific Aim 1, detailed metabolic phenotyping in LCR and HCR animals with a range of oxidative capacity will be performed at baseline and following exercise training. Physiologic, morphometric and metabolomic data will be evaluated.
In Specific Aim 2, a series of bioinformatic studies will be performed, including Bayesian analysis connecting gene expression, metabolome differences with phenotype to identify pathways and genes. Detailed promoter analysis will be performed to identify upstream factors that may underly differences in oxidative capacity in the LCR and HCR rats.
In Aim 3, temporal caloric restriction will be used to test the potential for 'metabolic imprinting'to alter the physiologic and biochemical profiles of the HCR and LCR animals in adulthood. These studies will provide a mechanistic understanding the contributions of 'nature'and 'nurture'in the development of insulin resistance and type 2 diabetes.
Individuals with a reduction in exercise capacity are known to be susceptible to obesity which can lead to insulin resistance, hypertension and in some, the development of type 2 diabetes. Exercise capacity is also a predictor of life expectancy. In the proposed studies we will use a systems biology approach in comparing animals bred to have low (LCR) or high (HCR) exercise capacity. The LCR rats have metabolic characteristics resembling obese humans while the HCR rats are lean and insulin sensitive. The studies are will combine the tools of metabolomics, genomics and bioinformatics to understand how metabolism is altered in these animals and what interventions can be useful to improve the health of the rats. The information obtained will be used to design more effective diet, exercise or drug therapy that will prevent the illnesses associated with obesity.
|Park, Young-Min; Rector, R Scott; Thyfault, John P et al. (2016) Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity. Am J Physiol Endocrinol Metab 310:E190-9|
|Park, Young-Min; Kanaley, Jill A; Zidon, Terese M et al. (2016) Ovariectomized Highly Fit Rats Are Protected against Diet-Induced Insulin Resistance. Med Sci Sports Exerc 48:1259-69|
|Rogers, Robert S; Morris, E Matthew; Wheatley, Joshua L et al. (2016) Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease. Diabetes :|
|Bowden-Davies, Kelly; Connolly, Joanne; Burghardt, Paul et al. (2015) Label-free profiling of white adipose tissue of rats exhibiting high or low levels of intrinsic exercise capacity. Proteomics 15:2342-9|
|Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G et al. (2015) Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome. PLoS One 10:e0126906|
|Overmyer, Katherine A; Evans, Charles R; Qi, Nathan R et al. (2015) Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. Cell Metab 21:468-78|
|Rosenblat, Mira; Volkova, Nina; Abassi, Zaid et al. (2015) High intrinsic aerobic capacity and pomegranate juice are protective against macrophage atherogenecity: studies in high- vs. low-capacity runner (HCR vs. LCR) rats. J Nutr Biochem 26:1015-21|
|Smyers, Mark E; Bachir, Kailey Z; Britton, Steven L et al. (2015) Physically active rats lose more weight during calorie restriction. Physiol Behav 139:303-13|
|Sollanek, Kurt J; Smuder, Ashley J; Wiggs, Michael P et al. (2015) Role of intrinsic aerobic capacity and ventilator-induced diaphragm dysfunction. J Appl Physiol (1985) 118:849-57|
|Vieira-Potter, Victoria J; Padilla, Jaume; Park, Young-Min et al. (2015) Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol 308:R530-42|
Showing the most recent 10 out of 43 publications