Leptin and Developmental Programming of Hypothalamic Autonomic Outflow

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PROJECT SUMMARY Despite a growing consensus that developmental programming of metabolic regulation contributes to the current obesity epidemic, our understanding of developmental mechanisms impacting this process remains rudimentary. The long range goal of this line of research is to define the developmental neurobiology of central pathways that contribute to developmental programming of metabolic phenotype. Maternal high fat diet (MHFD) exposure represents a developmental risk factor that contributes to metabolic dysregulation and impacts leptin sensitivity. MHFD also appears to impact leptin secretion, but it remains unknown whether it affects the developmental actions of leptin. For the proposed studies we will focus on neuronal pathways that connect the paraventricular hypothalamic nucleus (PVH) with two important components of the dorsal vagal complex (DVC): the dorsal motor nucleus of the vagus nerve (DMX) and the nucleus of the solitary tract (NTS), which regulate autonomic functions such as thermogenesis, energy expenditure and gastric motility. Inputs to the PVH from the NTS convey visceral sensory information, and inputs from the arcuate nucleus of the hypothalamus (ARH) and from the NTS convey hormonal signals. Integration of this information in the PVH impacts autonomic regulation through descending projections from the PVH to the DMX and NTS. However, it remains unknown if development of these connections is influenced by factors that program metabolic phenotype, such as MHFD and leptin. The overall hypothesis of the proposed research is that MHFD-L causes hyperleptinemia during a critical period of postnatal development that disrupts normal targeting of connections between the PVH and the DVC, and that the integrity of these connections is important for conveying signals that regulate distinct aspects of neuroendocrine physiology and autonomic function. Molecular genetic manipulation of leptin signaling, neuroanatomical methods, and physiological profiling will be used to address the following Specific Aims: 1) Define the impact of MHFD on formation of connections between the PVH and DVC in offspring, and document corresponding changes in postnatal leptin secretion and autonomic physiology; 2) Determine if leptin is required for development of bidirectional connections between the PVH and DVC; 3) Identify the site(s) of action, and physiological consequences, for developmental effects of leptin on formation of connections between the PVH and DVC. Completion of these aims will advance our understanding of how environmental signals program essential components of neural systems required to maintain normal metabolic physiology, and may identify novel therapeutic targets.