The development of obesity in the general population is a risk factor for the development of other serious diseases including Type II diabetes, coronary artery disease and hypertension each of which carries with them a significant risk of morbidity and mortality. The regulation of body weight is controlled by environmental and genetic influences that regulate both food intake and metabolism including thermogenesis. Central to the control of food intake is the adipocyte-secreted hormone leptin which acts through its receptor to regulate hypothalamic signaling. In addition, leptin also impacts on thermogenesis through its ability to regulate the production of thyrotropin-releasing hormone (TRH) whose production in the paraventricular nucleus is essential for normal thyroid hormone production. In addition, to being up regulated at the gene level by leptin, TRH message is down regulated by thyroid hormone. Thus, the TRH neuron in the hypothalamus provides an ideal system in which to examine gene regulation by two important pathways important in body weight regulation. To date there are no appropriate in vitro hypothalamic systems in which to examine the regulation of gene expression by both leptin and thyroid hormone. In the following application it is proposed to develop novel TRH secreting hypothalamic cell lines using both transgenic and retroviral technology which will allow to explore the mechanisms involved in the regulation of gene expression by leptin and thyroid hormone. In addition, these novel cell lines should give additional insight into hypothalamic development. It will also be examined in heterologous systems the exact transcriptional pathways by which leptin regulates TRH gene expression.
| Guo, Feifan; Bakal, Keren; Minokoshi, Yasuhiko et al. (2004) Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo. Endocrinology 145:2221-7 |
| Bjorbaek, Christian; Hollenberg, Anthony N (2002) Leptin and melanocortin signaling in the hypothalamus. Vitam Horm 65:281-311 |
