Hypothalamic substrates of metabolic imprinting

The mammalian brain develops according to intrinsic genetic programs that are influenced by a variety of environmental factors. Developing neural circuits take shape in two major environments: one in utero and a second during postnatal life. Although an abundance of epidemiological and experimental evidence indicates that nutritional variables during perinatal life have a lasting effect on metabolic phenotype, the underlying mechanisms remain unclear. Peripheral hormones are widely regarded as effective signals that reflect the state of peripheral environments and can directly influence the development of a variety of functional neural systems. Recent findings suggest that the adipocyte-derived hormone leptin may play an important role in directing formation of hypothalamic neural pathways that control body weight. The arcuate nucleus of the hypothalamus (ARH) is a key site for the regulatory actions of leptin in adults, and this same hormone is required for the normal development of ARH projections to other parts of the hypothalamus. In this review, the neurobiological role of leptin is considered within the context of hypothalamic development and the possibility that variations in both prenatal and postnatal nutritional environments may impact development of neural circuits that control energy metabolism through an indirect action on leptin secretion, or signaling, during key developmental critical periods.