The developing hypothalamus is exposed to two successive environments: one in utero and the other postnatal. As neural circuits form in the hypothalamus during these perinatal periods, environmental signals impact hypothalamic development in ways that impact homoeostasis throughout the life of the individual. Circuits that control body weight develop under the influence of the adipocyte-derived hormone leptin during discrete temporal domains, suggesting that there are region-specific, hormonally directed mechanisms governing the assembly of homeostatic circuits. Recent findings indicate that the ability of leptin to specify patterns of neuronal connectivity in the hypothalamus may differentially impact distinct components of autonomic regulation and glucose homeostasis. Moreover, leptin appears to exert these actions through direct neurotrophic influences on hypothalamic neurons that include promoting neurite extension, specifying patterns of axonal targeting, and influencing cell type specific alterations in synaptic density. Thus, leptin is a major developmental factor that may mediate metabolic programming of the hypothalamus by a variety of environmental factors, including nutrition. Currently, we are studying the organization and development of brain pathways that link the hypothalamus with the brainstem. Using genetically targeted fluorescent labels, and both in vitro and in vivo conditional regulation of gene expression, we are determining if manipulations of genes known to participate in brain development also influence the development of leptin-sensitive pathways that mediate hypothalamic responses to changes in energy balance. In addition, we are exploring epigenetic mechanisms that specify critical periods of brain development when leptin, and perhaps other environmental factors, impact brain architecture and the regulation of metabolic physiology throughout life.
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Key: MeSH Term KeywordAge Factors Agouti-Related Protein Analysis of Variance Animals Animals, Newborn Arcuate Nucleus of Hypothalamus Axons Bariatric Surgery brain development diabetes and obesity Diet, High-Fat ELAV-Like Protein 3 Estrogen Receptor alpha Female Green Fluorescent Proteins hypothalamus Hypothalamus Inflammation Integrases leptin Leptin Male metabolic programming Mice Mice, Inbred C57BL Mice, Transgenic Neurons Neuropeptide Y Obesity Receptors, Leptin STAT3 Transcription Factor