Maternal obesity increases the risk for offspring to become obese, and there is substantial evidence to suggest that programming during both fetal and neonatal development contributes to this predisposition. Breastfeeding, the recognized "gold standard" for human neonatal nutrition, is associated with reduced childhood obesity risk. However, emerging evidence from human and animal studies suggests that maternal obesity may override the benefits of breastfeeding on the metabolic health and obesity risk of nursing offspring. Our study is directed at understanding the mechanisms by which maternal obesity influences the metabolic predisposition of their off-spring to obesity. We established a mouse model that allows us to define postnatal contributions of maternal obesity to neonatal metabolic health and obesity predisposition, distinguishing the specific effects of maternal obesity from those imparted by maternal consumption of a high fat (HF) obesigenic diet. Our data document that milk from obese dams selectively programs obesigenic changes in neonatal metabolism. In recent work we linked these changes to impaired de novo milk lipid synthesis due to inhibition of acetyl- CoA carboxylase-1 (ACC1), and the production of lipid-poor milk by obese dams. The overall goals of this proposal are to use obese mouse models in conjunction with innovative genetic manipulation and quantitative metabolic and imaging approaches to: (1) define the effects of maternal obesity on off-spring obesity predisposition;(2) detail the effects of milk frm obese dams on neonatal metabolism;(3) define the roles ACC1 and de novo lipogenesis in the obesity-associated alterations in milk that promote neonatal obesity. The detailed systematic investigation of the physiological and molecular mechanisms underlying postnatal effects of maternal obesity on neonatal metabolic health, as outlined in this proposal, form the foundation for development of new intervention strategies to prevent obesity.
Childhood obesity and attendant metabolic disorders (insulin resistance, type II diabetes and metabolic syndrome) are at epidemic proportions in the United States, and increasing worldwide. Childhood obesity is associated with increased adult adiposity and elevated risk of chronic adult disease and mortality and concern is growing about the long-term health care burdens associated with increased incidences of childhood obesity. Although the in utero environment has been identified as a potentially critical source of maternal factors contributing to offspring obesity risk and future adult disease, there is increasing evidence that postnatal factors, particularly those in breast milk, may also influence offspring health outcome. Currently, little is known about how breast milk affects neonatal metabolism and obesity propensity and the factors within breast milk that influence neonatal metabolism have not been identified. Experiments in our study defining the fundamental metabolic properties of developing neonates and identifying how maternal obesity, diet and milk factors affect neonatal metabolic health, will provide new insight into the physiological determinants of childhood obesity.
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