Regulation of satiety and energy balance in Drosophila

CREB转录因子家族参与多种细胞功能，包括 能量平衡最近，一个新的CREB共活化剂家族，称为TORC，已经被发现。 鉴定TORC响应cAMP和钙信号易位到细胞核，其中 它们通过与CREB的直接相互作用增强细胞基因表达。果蝇有一个 单个TORC家族成员dTORC，其可以作为TORC家族的真正成员， 细胞培养共活化测定。TORC 1 +/-小鼠贪食，比野生小鼠体重增加更多 型的同窝仔，并显示高胰岛素血症。类似地，dTORC突变果蝇显示食物增加， 摄入量，改变糖原和甘油三酯储存，也显示出对饥饿的敏感性。这些 表型可以通过在神经系统中提供dTORC来拯救，这表明神经元的 dTORC活性对于调节食欲和能量储存至关重要。该提案旨在利用 果蝇了解TORC蛋白在这些过程中的功能。的结构域 将测试哺乳动物和果蝇之间保守的dTORC的功能。以来 dTORC在果蝇脑的胰岛素产生细胞中是活跃的，并且突变的dTORC果蝇具有 胰岛素途径改变预期的表型，dTORC 调节胰岛素的表达和信号传导。基因相互作用试验 胰岛素信号通路的组成部分将进行。dTORC变化的时间过程 将检查响应于进食和禁食的磷酸化状态和核穿梭。 除了胰岛素信号外，与饱腹感和能量储存有关的其他成分也可能 由dTORC和哺乳动物TORC控制。通过利用dTORC过表达 为了检测眼睛中的表型，将对增强或抑制表型的基因进行筛选， 贯彻这些基因可以编码dTORC信号传导途径的组分，并且通过 也延伸了哺乳动物TORCs的通路。

The CREB family of transcription factors participates in a variety of cellular functions including energy homeostasis. Recently, a new family of CREB coactivators, called TORCs, has been identified. TORCs translocate to the nucleus in response to cAMP and calcium signals, where they potentiate cellular gene expression via a direct interaction with CREB. Drosophila has a single TORC family member, dTORC, which can act as a bone fide member of the TORC family in cell culture coactivation assays. TORC1 +/- mice are hyperphagic, gain more weight than wild type littermates and show hyperinsulinemia. Similarly, dTORC mutant flies show increased food intake, altered glycogen and triglyceride stores, and also show sensitivity to starvation. These phenotypes can be rescued by supplying dTORC in the nervous system, indicating that neuronal dTORC activity is critical for regulation of appetite and energy stores. This proposal aims to use Drosophila to understand how TORC proteins function in these processes. The domains of dTORC that are conserved between mammals and Drosophila will be tested for function. Since dTORC is active in the insulin-producing cells of the fly brain and mutant dTORC flies have phenotypes expected from alteration of the insulin pathway, the hypothesis that dTORC regulates insulin expression and signaling will be tested. Tests for genetic interactions with insulin signaling pathway components will be carried out. The time course of changes in dTORC phosphorylation state and nuclear shuttling in response to feeding and fasting will be examined. In addition to insulin signaling, other components involved in satiety and energy stores are likely to be controlled by dTORC and mammalian TORCs. By capitalizing on a dTORC overexpression phenotype in the eye, a screen for genes that enhance or suppress the phenotype will be carried out. These genes may encode components of the dTORC signaling pathway, and by extension the pathway for mammalian TORCs as well.