Exercise Regulation of Glucose Homeostasis

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PROJECT SUMMARY/ABSTRACT The overall hypothesis of this project is that regular physical exercise in mothers is critical for the prevention of type 2 diabetes and metabolic disease in offspring. Our mouse studies establish that maternal exercise before and during pregnancy has striking beneficial effects on the metabolic health of both male and female offspring. These findings have opened a new area of exercise physiology research, suggesting that exercise is an important tool to combat the development of type 2 diabetes, and underscores the need for scientific investigation aimed at determining the molecular mechanisms by which maternal exercise improves metabolic health of offspring. For this purpose, and based on our extensive published and preliminary data, we have defined four Specific Aims. Specific Aim 1 will investigate the vitamin D receptor (VDR) and TGF2 as central mediators of maternal exercise effects on offspring metabolic health in liver, skeletal muscle, and other offspring tissues. This includes experiments that will: a) determine the function of VDR in maternal exercise- induced hepatic, skeletal muscle, and adipose tissue AMPK/TET signaling, epigenetic changes, and in vivo glucose homeostasis; b) investigate TGF2 as a maternally derived exercise signal that activates epigenetic changes and improves offspring phenotype; and c) determine if maternal exercise has wide ranging effects to improve the function of skeletal muscle and adipose tissues. Specific Aim 2 will determine optimal exercise and pharmacologic treatments for the improvement of offspring metabolic health. This includes experiments to define: a) optimal maternal exercise protocols to improve metabolic health; and b) pharmacologic activators that mimic the beneficial effects of maternal exercise on offspring health. Specific Aim 3 is to identify and determine the function of novel exercise regulated placental proteins that improve the metabolic health of offspring, as our initial findings established that placenta is central to transmitting the effects of maternal exercise to offspring. Aim 3 experiments include: a) investigation of novel placental secretory proteins increased by maternal exercise; b) fetal tissue destination of these proteins; and c) investigating maternal exercise effects on placenta spatial and single cell transcriptomics. We have recently made the exciting discovery that grandmaternal exercise improves the metabolic health of second generation (F2) offspring in adulthood. Specific Aim 4 will determine the mechanisms by which grandmaternal exercise training enhances F2 offspring health. This will include investigating: a) maternal exercise effects on F1 sperm and oocytes; b) mechanisms for improved glucose tolerance in F2 offspring, including studies of skeletal muscle glucose uptake; and c) effects of grandmaternal exercise on epigenetic regulation of skeletal muscle, liver, and adipose tissue in F2. This emerging area of exercise physiology research has great potential to advance world health by understanding mechanisms by which exercise during female reproductive years may limit the vicious cycles of increased metabolic risk across multiple generations.