As children enter early adolescence, cardiovascular and metabolic consequences of obesity become more apparent. Studies in older children show that obesity and central fat distribution are associated with these outcomes. But how did the children get there in the first place? This is a key question for chronic disease prevention. A now-vast animal experimental literature and a growing human counterpart demonstrate that factors operating at the earliest stages of human development-even before birth-can have lifelong consequences for obesity and cardiometabolic outcomes. Yet major questions still exist regarding how pre- and peri-natal factors operate, through gain in weight and adiposity, to influence these outcomes. In analyses from the previous cycle of Pre- and peri-natal predictors of childhood obesity, the findings imply both that the endocrine milieu at the time of birth is different from later in life, and that it is likely to be a key driver of weight gain in the first months of life, itself a strong predictor of later obesity and cormorbidities. While these observations are consistent with endocrine knowledge emerging from animal experiments, they raise several questions: 7 To what extent are prenatal factors such as maternal nutrition (e.g., fatty acids, vitamin D), smoking, gestational weight gain, and gestational diabetes associated with perinatal hormone levels? 7 What other hormones are involved in these pathways? In particular, what are the roles of insulin and insulin-like growth factors (IGFs), which are correlated with leptin levels? 7 If these hormones influence childhood weight gain, do they also influence gain in adiposity, fat distribution, components of the metabolic syndrome and vascular dysfunction in early adolescence? 7 To what extent are these influences mediated by adiposity-related inflammation? The overall goal of this renewal of R01 HD 034568-10 is to examine associations of potentially modifiable prenatal factors, hormone levels in umbilical cord blood, gains in weight and adiposity in childhood, adiposity- related inflammation, and cardiometabolic outcomes in early adolescence. including components of the metabolic syndrome, carotid intima-media thickness, and endothelial dysfunction. Extending the productive pre-birth cohort study Project Viva through the age of 11 years provides the opportunity to meet this challenge. The results of this research will lead to new scientific knowledge about the drivers of growth and adiposity in childhood and may very well lead to new avenues for prevention of obesity, diabetes, and cardiovascular disease. PUBLIC HEALTH RELEVANCE: As children enter early adolescence, the harmful cardiovascular and metabolic effects of obesity become more apparent. The drivers of these health outcomes may exist very early in life, perhaps even before birth. In this renewal of the grant that originally funded the cohort study Project Viva, we will examine how maternal diet, smoking, weight gain and diabetes during pregnancy affect hormone levels around the time of birth, how these hormone levels are associated with patterns of growth and inflammation during childhood and in turn with heart disease and diabetes risk factors at the age of 11 years. Our results will lead to new scientific knowledge and may very well lead to new ways to prevent obesity, diabetes, and cardiovascular disease.