Diet Obesity and Developmental Programming.

Lead Research Organisation: King's College London
Department Name: Reproduction and Endocrinology


The global epidemic of obesity contributes significantly to the burden of cardiovascular disease. Converging lines of evidence, from both human and animal studies, suggest that the origins of obesity and related metabolic disorders can be found in the interplay between genes and the embryonic, fetal and neonatal environment. Obesity in pregnancy increases the risk of poor pregnancy outcome including pre-eclampsia, gestational hypertension, and gestational diabetes mellitus. However, the consequences of maternal obesity are now thought to extend beyond poor obstetric outcome to persistent effects on the offspring, notably an increase in the risk of obesity and metabolic syndrome in adulthood. Researchers at King's have developed a novel mouse model of maternal obesity in pregnancy, which programmes hyperphagia (increased appetite), hyperadiposity and insulin resistance in adult offspring despite a healthy diet from weaning. Using this rodent model this proposal aims to investigate the mechanisms whereby obesity in pregnancy can permanently alter offspring metabolism and energy balance in adulthood. Plasma profiles during pregnancy and suckling implicate maternal hyperglycaemia and dyslipidaemia as potential programming vectors in the transmission of an obesogenic and diabetogenic trait to the next generation. Tate & Lyle is currently developing ingredient solutions under its ENRICH service, which aims to enhance the nutritional benefit of food and beverages to address current health issues such as obesity and weight management. Key to these goals, is the utilisation of carbohydrate, fibres and proteins to promote satiety and sustain slower glucose release into the blood stream. It is hypothesised that dietary intervention with complex starches in the mouse model will improve plasma profiles in pregnancy and suckling and prevent the development of a metabolic syndrome-like phenotype in the adult offspring. This project will investigate the effect of dietary intervention in pregnancy on glucose homeostatsis, central insulin resistance, and energy balance in both obese dams and their offspring and thereby interrogate the underlying mechanisms in the developmental programming of altered energy balance. To investigate energy intake and expenditure, we will use the Comprehensive Laboratory Animal Monitoring System (CLAMS). This system enables study of both components of energy balance (i.e. intake and expenditure). Food intake, meal frequency, activity and energy expenditure including Respiratory Exchange Ratio (by indirect calorimetry) are recorded over a 72-hour period. The non-invasive nature of this methodology enables assessment in the same animals at each time point thus facilitating longitudinal study. Body composition will be determined by MRI (KCL, Division of Imaging Sciences). In view of the proposed role of central insulin resistance in the development of obesity, pilot studies will determine the use of PET scanning of mouse brains as a method of assessment of central insulin resistance and appetite control. This will involve the use of radio-labelled tracer 18 fluoro-deoxyglucose which provides the opportunity to characterise patterns of neural activity in the brain by PET. CT scanning co-registered on the PET image provides anatomical landmarks that allow imaging of regional brain activity including quantitative changes in the hypothalamus.The improved management of obesity in pregnancy is essential for the health of future generations and this realistic dietary approach employing complex starches to modulate the gene-environment interactions in embryonic and fetal life will extend our understanding of developmental programming mechanisms in early life and could readily translate to effective public health strategies to stem the growing tide of obesity.


10 25 50