Physiological Underpinnings of High Voluntary Exercise in Selectively Bred Mice: Effects of Western Diet

Obesity is a growing health problem worldwide, particularly within the United States. The percent of both overweight and obese Americans (~2/3 combined as of surveys completed in 1999-2004) has continued to increase over the past two decades. Exercise is a cornerstone for the treatment of obesity, and understanding the regulation of energy balance in response to exercise is essential for the prevention of obesity and the metabolic syndrome. Using lines of house mice that have been selectively bred for high voluntary wheel running (high runner [HR]) and their non-selected control lines, I have characterized changes in both ability to exercise and propensity to exercise, both of which, at least in humans, can independently impact mortality rates. The increased endurance capacity observed in the four replicate high runner lines of mice provides evidence of a genetic correlation between the ability and propensity for aerobic exercise. However, this genetic advantage does not appear to confer resistance to diet-induced obesity or key components of the metabolic syndrome. But the elevated running behavior of HR mice does reduce susceptibility to diet induced obesity. In an 8-wek study, I found that circulating blood lipids are not affected by wheel running in either high runner or control mice, but gain of fat mass is greatly reduced by wheel access, even when animals are eating a Western diet, high in fat and with added sucrose. I also found an unprecedented genotype-by-environment interaction. High runner mice showed a remarkable increase in wheel running when given Western diet, whereas wheel running of control mice was unaffected. Based on results from skeletal muscle enzyme assays, molecular levels of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, the increase in running is likely related more to central nervous system fatigue or motivation rather than the availability of lipid substrates as an energy source. In conclusion, my research provides further evidence of important genetic differences between the high runner lines of mice and their non-selected controls, further elucidating how athletic performance evolves. My results also demonstrate the importance of genotype-by-environmental interactions, which are likely to account for a substantial fraction of the differences among individuals for many complex phenotypes, including energy balance, obesity, and voluntary exercise. Understanding these interactions will likely prove essential for stopping and reversing the current trends in human obesity and many other complex human diseases