Grant: Project Grant - PA: Nutrition, Metabolism and Diabetes

Human growth hormone is released into the circulation with highs (at night) and lows (in the day) on a daily basis. Levels are highest during puberty to help provide the energy from fats and sugars for children going through a growth spurt. Part of the way growth hormone helps maintain energy levels is by helping to make sure there are enough insulin producing cells in the pancreas. If you are not able to make enough insulin you will develop diabetes. Studies of growth hormone production, particularly in children and young adults, are limited as pituitaries are not normally available until after death. Use of animals is not optimal, as human and, for example, rodent growth hormones are not the same. Thus, we generated mice with the human growth hormone gene and showed that overeating in puberty negatively affects chromosome structure and specifically a loop of protein and DNA containing the human growth hormone gene, which is needed for efficient growth hormone production. As a result, daily growth hormone levels decreased to those seen in much older mice on a regular diet. However, if the mice were made to increase physical swim activity, the negative effects of overeating on the loop and growth hormone production were lost. We will now study whether changes in daily growth hormone production that were seen as a result of overeating and forced swimming are related to effects of insulin and glucocorticoid hormones, respectively, and identify the downstream protein factors that help maintain or disrupt the loop, which acts as a control 'hub'. These factors are expected to offer a target to resist or repair the negative impact of overeating and help maintain responsiveness of the growth hormone gene, by increasing or lowering their levels. We will also develop a new mouse model to test whether loss of growth hormone signals to the pancreas in puberty directly leads to increased risk for diabetes.