Perinatal programming and functional teratogenesis: Impact on body weight regulation and obesity

It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic, and hormonal environment may cause predispositions for the development of diseases in later life. Studies in the offspring of diabetic mothers have decisively contributed to this perception. Alterations of the fetal and neonatal environment which offspring of diabetic mothers 'experience' seem to program a disposition to develop obesity, diabetes mellitus and Syndrome X-like alterations throughout later life. Underweight at birth is also suggested to lead to an increased risk of Syndrome X in later life ('Barker hypothesis'). Pathophysiological mechanisms are unclear. Hormones are important environment-dependent organizers of the developing neuro-endocrine-immune network, which finally regulates all fundamental processes of life. When present in non-physiological concentrations during 'critical periods' of perinatal life, induced by alterations in the intrauterine or neonatal environment, hormones can act as 'endogenous functional teratogens'. Perinatal hyperinsulinism is pathognomonic in the offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or only intrahypothalamic insulin treatment during perinatal development, may lead to 'malprogramming' of neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. In conclusion, a complex malprogramming of the central regulation of body weight and metabolism may provide a general etiopathogenetic concept, explaining perinatally acquired dispositions, thereby opening a wide field of primary prevention.