The rates of obesity and type 2 diabetes are increasing at alarming rates in the United States and throughout the world. Regular physical activity can prevent or delay the onset of type 2 diabetes, and at least part of the mechanism for these important effects of exercise is the beneficial role it plays on whole body and tissue glucose homeostasis. The long-term goal of this project is to understand the molecular mechanisms by which exercise exerts beneficial effects on glucose homeostasis and metabolic health. Emerging data now suggest that exercise performed by mothers before and during pregnancy can have important beneficial effects on offspring health. While it has been known that suboptimal maternal diets, such as a high fat diet, can negatively affect offspring health, the effects of maternal exercise have not been well explored. Studies from the current funding cycle of this award have established that maternal (F0 generation) exercise training improves offspring (F1 generation) metabolic health, including glucose tolerance and insulin sensitivity, and can abolish the detrimental effects of maternal high fat feeding on offspring metabolic health. Interestingly, these studies found that paternal exercise also has profound effects on offspring (F1) metabolic health, ameliorating the detrimental effects of paternal high fat feeding on offspring glucose tolerance, fat mass, and hepatocyte glucose production. Mouse studies have shown that improved metabolic function of the liver appears to be a major mechanism mediating the beneficial effects of maternal exercise on offspring health. For paternal exercise, preliminary data suggest that adaptations to both liver and muscle are major mechanisms for the beneficial effects of paternal exercise on offspring health. The focus of this project for the coming five years is to understand the mechanisms underlying these beneficial effects. There is also evidence that the detrimental effects of poor maternal (F0) diet can propagate through multiple generations (F2). Whether maternal exercise can reverse these detrimental effects of diet on later generations of offspring (F2) is not known. The overall hypothesis of this project is that maternal and paternal exercise training improves whole-body and tissue metabolism in male and female offspring and that epigenetic modifications mediate these important effects of exercise. There are three specific aims: 1) To determine the mechanisms by which maternal exercise training improves the metabolic phenotype of F1 offspring liver, 2) To determine the effects of grand-maternal exercise training on F2 metabolic health, 3) To determine the effects of paternal exercise training on F1 offspring metabolic health. These studies could result in a new paradigm whereby maternal and paternal exercise are viewed as central in promoting the metabolic health of offspring, reducing the risk of type 2 diabetes in future generations.
The incidence of type 2 diabetes continues to escalate worldwide, and there is increasing evidence that undesirable environmental factors such as poor nutrition can increase the risk for transmission of this disease from parents to offspring by changes that are independent of the DNA code. It is well established that regular physical activity can prevent or delay the onset of type 2 diabetes, and the long term goal of this project is to understand the molecular mechanisms through which exercise improves glucose homeostasis and metabolic health. The specific focus of this research project for the next five years is to determine if maternal and paternal exercise can function as a beneficial environmental factor that can improve the metabolic health of offspring and grand-offspring, which could provide a new paradigm for diabetes prevention, and have a tremendous impact on health care worldwide.
|Stanford, Kristin I; Rasmussen, Morten; Baer, Lisa A et al. (2018) Paternal Exercise Improves Glucose Metabolism in Adult Offspring. Diabetes 67:2530-2540|
|Lessard, Sarah J; MacDonald, Tara L; Pathak, Prerana et al. (2018) JNK regulates muscle remodeling via myostatin/SMAD inhibition. Nat Commun 9:3030|
|Mul, Joram D; Soto, Marion; Cahill, Michael E et al. (2018) Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ?FosB. Neuropsychopharmacology 43:1934-1942|
|Stanford, Kristin I; Takahashi, Hirokazu; So, Kawai et al. (2017) Maternal Exercise Improves Glucose Tolerance in Female Offspring. Diabetes 66:2124-2136|
|May, Francis J; Baer, Lisa A; Lehnig, Adam C et al. (2017) Lipidomic Adaptations in White and Brown Adipose Tissue in Response to Exercise Demonstrate Molecular Species-Specific Remodeling. Cell Rep 18:1558-1572|
|Laker, Rhianna C; Drake, Joshua C; Wilson, Rebecca J et al. (2017) Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun 8:548|
|Mul, Joram D; Zheng, Jia; Goodyear, Laurie J (2016) Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice. eNeuro 3:|
|Lerin, Carles; Goldfine, Allison B; Boes, Tanner et al. (2016) Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab 5:926-936|
|Mul, Joram D; Stanford, Kristin I; Hirshman, Michael F et al. (2015) Exercise and Regulation of Carbohydrate Metabolism. Prog Mol Biol Transl Sci 135:17-37|
|Stanford, Kristin I; Lee, Min-Young; Getchell, Kristen M et al. (2015) Exercise before and during pregnancy prevents the deleterious effects of maternal high-fat feeding on metabolic health of male offspring. Diabetes 64:427-33|
Showing the most recent 10 out of 12 publications