REVIEW Developmental origins of health and disease: experimental and human evidence of fetal programming for metabolic syndrome ML de Gusma ˜o Correia, AM Volpato, MB A ´ guila and CA Mandarim-de-Lacerda Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil The concept of developmental origins of health and disease has been defined as the process through which the environment encountered before birth, or in infancy, shapes the long-term control of tissue physiology and homeostasis. The evidence for programming derives from a large number of experimental and epidemiologi- cal observations. Several nutritional interventions dur- ing diverse phases of pregnancy and lactation in rodents are associated with fetal and neonatal program- ming for metabolic syndrome. In this paper, recent experimental models and human epidemiological stu- dies providing evidence for the fetal programming associated with the development of metabolic syndrome and related diseases are revisited. Journal of Human Hypertension (2012) 26, 405 – 419; doi:10.1038/jhh.2011.61; published online 23 June 2011 Keywords: fetal programming; developmental origins of disease; metabolic syndrome; obesity Introduction The concept of developmental origins of health and disease (a.k.a. fetal programming) was first proposed by David Barker 1 and later defined by Alan Lucas 2 as the permanent response of an organism to a stimulus or insult during critical periods of development. The concept of programming was later expanded and defined as the process through which the environment encountered before birth, or in infancy, shapes the long- term control of tissue physiology and homeostasis. 3 Such adaptive responses often cause several diseases in adult life. The evidence for fetal programming comes from a large number of experimental and epidemiolo- gical observations. Barraclough 4 demonstrated that neonatal administration of testosterone to female rats causes ovulation failure and sterility, which are not observed if the hormone is given later in life. Importantly, Rose et al. 5 first reported that the risk of ischaemic heart disease doubled in human subjects whose siblings were still born or died in early child- hood, suggesting that adverse exposures during preg- nancy could cause diseases in adulthood. Metabolic syndrome is an aggregation of risk factors (that is, overweight, abdominal obesity, hypertension, dyslipidaemia and glucose intoler- ance) that strongly correlates with cardiovascular disease. Several nutritional interventions during diverse phases of pregnancy and lactation in rodents are associated with fetal and neonatal programming for metabolic syndrome. In humans, both small and large for gestational age newborns have been shown to develop features of metabolic syndrome during growth and adulthood. In this paper, recent experimental and epidemiolo- gical studies providing evidence for the fetal pro- gramming associated with the development of metabolic syndrome and related diseases were re- viewed. First, associations between birth weight and the increase in cardiovascular risk in humans based on epidemiological observations were discussed. Second, we revisited evidence linking maternal low- protein diet with development of metabolic syndrome in rodents. Finally, recent experimental studies showing the effects of maternal overnutrition in the adult offspring were presented. Cardiovascular risk and fetal program- ming in humans: early evidence Several epidemiological reports have shown asso- ciations between prenatal and postnatal exposures and the development of metabolic syndrome in adult life. Although genomically imprinted genes Received 13 May 2010; revised 20 February 2011; accepted 9 May 2011; published online 23 June 2011 Correspondence: Professor ML de Gusma ˜o Correia, Laboratory of Morphology, Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Boulevard 28 de Setembro, 87 fds, 20551-030 Rio de Janeiro, RJ, Brazil. E-mail: marcelo_correia@yahoo.com Journal of Human Hypertension (2012) 26, 405–419 & 2012 Macmillan Publishers Limited All rights reserved 0950-9240/12 www.nature.com/jhh