Both genetic and environmental factors impact metabolic programming and leptin has been identified as a potent neurotrophic factor that functions during perinatal life to specify patterns of connectivity in the hypothalamus. Raising mice in large litters abolishes the normally occurring postnatal surge in leptin secretion and results in increased adiposity, rapid catch up growth rates after weaning, increased insulin resistance, and perturbations in neural projections from the arcuate nucleus of the hypothalamus (ARH). During hypothalamic development, axons extend from the ARH to form synaptic contacts with neurons in the paraventricular nucleus of the hypothalamus (PVH), which contains cells known to mediate multiple aspects of energy balance regulation. Leptin plays an important role in directing development of ARH projections to the PVH, with accompanying effects on establishing levels of leptin sensitivity and food intake. Moreover, alterations in fatty acid composition during postnatal nutrition also alter development of projections from the ARH to the PVH. Leptin acts during a defined period of circuit development with both cell type and target specificity, and closure of this critical period occurs differently in males and females. The ventromedial hypothalamic nucleus (VMH) also plays an important role in regulating energy balance and we recently identified BDNF as an important factor required for normal development of VMH connectivity and glucose homeostasis. Together these findings suggest that leptin, nutrition and BDNF act during development to specify patterns of hypothalamic neural circuitry that impact distinct aspects of neuroendocrine regulation.