Childhood obesity has increased in the United States and internationally, which sets up young people for a lifetime of devastating and costly health problems. The neural networks that regulate metabolic homeostasis must develop appropriately in order to function properly in adulthood. Neural circuits that develop under abnormal environmental conditions can become disrupted and no longer function normally, which can lead to obesity and associated negative health consequences. The nucleus of the solitary tract (NTS) in the hindbrain receives and integrates visceral nutritional status, and primarily sends this information to the paraventricular nucleus of the hypothalmus (PVH), which coordinates energy balance and neuroendocrine responses. Leptin receptors (LepRb) in NTS neurons have been shown to impact food intake and metabolic rate. In addition to leptin's role in satiety signaling, it also functions as a neurotrophic factor in development. Leptin is required for normal axon outgrowth from the arcuate nucleus of the hypothalamus to the PVH. Because leptin receptors are expressed by neurons in the NTS during development (including a large proportion of GLP-1 neurons), leptin may direct formation of this pathway. Experiments proposed in Specific Aim 1 will test whether leptin is required for normal development of neural projections from GLP-1 neurons in the NTS to the PVH. Genetically targeted axonal labels and immunohistochemistry will be used to visualize and quantify GLP-1 neurons in the NTS and their projections in leptin-deficient Lepob/ob mice in development and adulthood. Experiments proposed in Specific Aim 2 will utilize a molecular genetic approach to establish the site of action for leptin's neurotrophic action on NTS GLP-1 neurons and characterize the physiological role of this pathway. Together these studies promise to establish the GLP-1 projection pathway from the NTS to the PVH as a developmentally programmable substrate that determines significant aspects of metabolic physiology.
The prevalence of childhood obesity is observed at very high rates, leading to several costly negative health outcomes. Development of neural circuits in the brain that regulate metabolic homeostasis is sensitive to deleterious effects of environmental signals, which may render young people at risk for a lifetime of poor health. The goal of this proposal is to determine the role of the adipocyte-derived hormone leptin on development of neural pathways within the brain, which may provide new strategies for treating obesity early in life.
