Location: Healthy Body Weight Research
Project Number: 3062-51000-052-000-D
Project Type: In-House Appropriated
Start Date: Oct 1, 2014
End Date: Jun 4, 2019
Obesity and obesity risk are perpetuated across generations. DNA alterations that occur in utero are capable of inducing changes in gene expression that are sustained throughout the life span. Understanding maternal factors that establish an embryonic and fetal environment that promote obesigenic epigenetic changes is vital to developing maternal health habits that will reduce obesity risk across generations. The overarching goal of this project is to determine the mechanisms by which the maternal diet, maternal obesity, and maternal aerobic exercise modify the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes in the subcutaneous, visceral and intermuscular (skeletal muscle) fat depot of offspring. The project will utilize animal models and translation to a human study to investigate epigenetic transmission of beige adipocyte differentiation and lipid metabolism as causes of obesity risk across generations. Objective 1: Determine the mechanisms by which high fat in the maternal diet and a high fat diet and exercise in the offspring influence the regulation of adipose tissue and muscle energy metabolism in the offspring. Objective 2: Determine the effects of human maternal obesity and exercise participation during pregnancy on DNA methylation, energy metabolism and adipocyte tissue regulation of women and their infants.
The maternal consumption of excess food energy leading to maternal obesity contributes to the subsequent development of obesity in offspring. This phenomenon, in part, involves the epigenetic transmission of obesity risk across generations. The overarching hypothesis of this proposal is that a maternal high fat diet and maternal obesity increase the risk of development of obesity in offspring by reducing the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes in the offspring. To identify anti-obesity strategies, this project will first determine mechanisms of how excess maternal energy intake via high fat diets contributes to programming of epigenetically imprinted genes that control oxidation of lipids in subcutaneous fat and intermuscular (skeletal muscle) fat depots of offspring, thus contributing to offspring obesity. Effects of interventions, aerobic exercise and replacement of high dietary saturated fat with n-3 polyunsaturated fatty acids (n3-PUFAs), will be tested to determine whether these interventions have beneficial effects on reducing offspring obesity by promoting the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes. The common focus across all studies is obesity-associated increases in insulin and insulin-like growth factor 1 and 2 concentrations and their role in modulating differentiation of beige adipocytes via activation of a key transcription factor involved in beiging, PR domain containing 16 (PRDM16). The main hypothesis is that maternal obesity and a high saturated fat diet induce offspring obesity and type 2 diabetes mellitus (T2DM) by inhibiting PRDM16 activation and beige adipocyte differentiation resulting in decreased lipid oxidation and increased fat storage. The second hypothesis is that exercise and replacement of saturated fat diet partially with n-3 PUFA decrease IGF1 and 2 and insulin to restore PRDM16 activation and beige adipocyte differentiation. This project will test these hypotheses, using a combination of animal model studies and a pilot human intervention trial. These results will inform diet and exercise guidelines for pregnant women to the end of optimizing the long-term health of their children.