Transcriptional regulation of agouti-related protein.

摘要

Energy homeostasis is mediated by a hypothalamic control center that receives input from leptin, an adipocyte-derived hormone whose circulating levels reflect energy stores. Leptin acts directly on hypothalamic neurons to regulate neuronal activity and neuropeptide gene expression. Neurons producing Agouti-related Protein (Agrp), a neuropeptide which stimulates food intake, are targets of leptin action. Agrp gene expression in the brain is restricted to the hypothalamus and is elevated by deficits in energy balance communicated by leptin. Understanding how leptin regulates Agrp expression is an important goal with potential implications for the treatment of pathologic disorders of energy balance.; In Agrp neurons, leptin activates the transcription factor Signal Tranducer and Activator of Transcription-3 (Stat3), suggesting a role for Stat3 in the regulation of Agrp expression. This thesis aims to identify Agrp regulatory regions and to use them as a tool for studying Agrp transcription and Stat3 signaling in Agrp neurons. We characterize an Agrp regulatory region that recapitulates both fasting-responsive and cell-type specific aspects of Agrp expression in transgenic mice, and we apply an extension of this observation to study the potential role of Stat3 in Agrp neurons. As a complimentary approach, we use multi-species comparative sequence analysis to detect evolutionarily conserved sequences within the Agrp regulatory region which may function in Agrp transcripitional regulation.; This work provides in vivo evidence which demonstrates a role for specific sequence elements in the regulation of Agrp and which offers a modified perspective on Stat3 function in Agrp neurons. In addition, our approach is generally applicable for further genetic analysis of this important neuronal population.