Start Date: Oct 01, 2014
End Date: Sep 30, 2019
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.