Background:The combination of maternal obesity in early pregnancy and high protein intake in infant formula feeding might predispose to obesity risk in later life. Methods: This study assesses the impact of breast-or formula-feeding (differing in protein content by 1.65 or 2.7 g/100 kcal) on the metabolism of term infants from overweight and obese mothers. From birth to 3 mo of age, infants received exclusively either breast-or starter formula-feeding and until 6 mo, exclusively either a formula designed for this study or breast-feeding. From 6 to 12 mo, infants received complementary weaning food. Metabonomics was conducted on the infants' urine and stool samples collected at the age of 3, 6, and 12 mo. results: Infant formula-feeding resulted in higher proteinderived short-chain fatty acids and amino acids in stools. Urine metabonomics revealed a relationship between bacterial processing of dietary proteins and host protein metabolism stimulated with increasing protein content in the formula. Moreover, formula-fed infants were metabolically different from breast-fed infants, at the level of lipid and energy metabolism (carnitines, ketone bodies, and Krebs cycle). conclusion: Noninvasive urine and stool metabolic monitoring of responses to early nutrition provides relevant readouts to assess nutritional requirements for infants' growth. c oncurring with the obesity epidemic, maternal obesity is rising (1), with subsequent increased risk of childhood overweight and obesity for the offspring of overweight and obese women (2,3). This increasing mother/child metabolic disease risk is driven by both genetics and pre/postnatal environmental factors (4). Since childhood overweight is a strong predictor of adult obesity, increased infant metabolic disease may translate into severe health consequences for the same subjects in adulthood (5,6). Although causality is not established, rapid growth in infancy is associated with later overweight and obesity (3,7). Therefore, any measure that could reduce the risk of later obesity would be of particular importance for infants born to overweight mothers, including reduction in rapid weight gain in infancy.Optimal prenatal nutrition can reduce the risk of obesity in adults by influencing birth weight (5). Moreover, breast-feeding and introduction of complementary foods adapted to both metabolic and nutritional requirements of growing infants are also envisioned as preventive measures against obesity later in life (5). Alteration of nutrition in a critical period of development in early life can affect the subsequent pattern of growth and development of tissues and organs and may predispose individuals to several disorders later in life (8,9). Interestingly, in the study conducted by Li et al. (10), breast-feeding seems to reduce the risk of being overweight during childhood in infants from obese mothers. On the other hand, obese women have difficulties in initiating and maintaining breast-feeding (11,12) likely because of defects in their hormonal response to suckling (11,12), b...