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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01DK101043-17S1
Application #
8807155
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
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
An, Ding; Lessard, Sarah J; Toyoda, Taro et al. (2014) Overexpression of TRB3 in muscle alters muscle fiber type and improves exercise capacity in mice. Am J Physiol Regul Integr Comp Physiol 306:R925-33