The rates of obesity and type 2 diabetes are increasing at alarming rates in the United States and throughout the world. There is increasing evidence that 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 of exercise 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. Studies from the current funding cycle of this award have used various mouse models to elucidate novel signaling proteins involved in exercise-stimulated glucose transport including the AMPK-related kinases SNARK, QSK, and BRSK1, the actin motor protein Myo-1c, and the calcium mediated protein CaMKII. The focus of this project for the coming five years is to test the hypothesis that exercise-training before and during pregnancy has profound effects on whole body and tissue insulin sensitivity in adult offspring. While maternal obesity and over-nutrition are established risk factors for obesity and the development of type 2 diabetes in offspring, little is known about the long-term effects of maternal exercise on offspring health. Preliminary mouse studies generated during this funding cycle have shown that maternal exercise can abolish the development of glucose intolerance, increased fasting insulin concentrations, insulin resistance, and increased body fat in offspring at one year of age, even if the mother consumed a high-fat diet. These profound effects of maternal exercise on offspring metabolic health, along with the potential clinical significance of these findings for human health, provide strong rationale for the proposed studies. The overall hypotheses of the proposed work are that maternal exercise improves whole body and tissue glucose homeostasis in offspring and that epigenetic modifications to liver and skeletal muscle mediate these important effects of exercise on glucose homeostasis. There are four specific aims: 1) To determine the effects of maternal exercise on whole body metabolic homeostasis in offspring;2) To determine if offspring of trained dams have a more advantageous response to dietary and exercise manipulations;3) To determine the role of the liver in the effects of maternal exercise to improve the metabolic phenotype of offspring;and 4) To determine the role of skeletal muscle in the effects of maternal exercise to improve the metabolic phenotype of offspring. The use of state-of-the art physiological assessments in combination with cutting-edge genomic technologies will provide a powerful approach for elucidation of physiological mechanisms underlying the important effects of maternal exercise on offspring health. Eventual translation of these studies to the human population will be important for worldwide public health.

Public Health Relevance

While the incidence of type 2 diabetes continues to escalate worldwide, there is increasing evidence that regular physical activity can prevent or delay the onset of this disease. The goal of this project is to understand the molecular mechanisms through which exercise improves glucose homeostasis and metabolic health, with a specific focus for the next five years to determine how exercise before and during pregnancy improves skeletal muscle metabolism and glucose homeostasis in offspring. Translational research resulting from these basic exercise science studies could provide a new paradigm for diabetes prevention and have a tremendous impact on health care worldwide.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Silva, Corinne M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
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