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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Castle, Arthur
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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