脂肪米色化在能量代谢调控中发挥了重要作用。转录水平对产热基因表达的调节和β-肾上腺素受体信号通路的激活是调控脂肪米色化的主要途径。mTORC1是能量代谢的中枢传感器，但它相关的信号通路对脂肪米色化的调节作用还存在较大的争议。我们的前期研究发现mTORC1信号的负调节因子应激反应蛋白DDIT4的表达受冷刺激和β-肾上腺素受体信号通路调控，且DDIT4可能参与了脂肪细胞产热基因的表达调控，然而其中的作用机制和调控网络还不清楚。在本项目中，我们计划通过 “gain-of-function”和“lose-of-function” 的研究策略及脂肪组织特异性敲除的细胞和动物模型，通过分子、细胞和动物整体水平的研究，深入探讨脂肪DDIT4在调控产热基因表达和介导β-肾上腺素受体和mTORC1信号通路之间的相互作用和分子网络调控产热和脂质代谢的作用。课题的开展将为糖脂代谢调控提供新思路和新策略。

Adipose tissue browning plays an important role in energy homeostasis. Transcriptional regulation of thermogenic genes and activation of β-adrenergic signaling are important ways in the control of browning. mTORC1 is a key energy sensor in cell, however, the role of mTORC1 associated pathway in the regulation of browning is quite controversial. DNA Damage Inducible Transcript 4 (DDIT4) is a stress response protein and a negative regulator of mTORC1 signaling. Our preliminary data show that the expression of DDIT4 is induced by the activation of β-adrenergic signaling and, importantly, knockdown of DDIT4 lead to suppression of thermogenic gene expression, indicating that it may be involved in the regulation of thermogenic gene expression, however, the underlying mechanism is unknown. In this project, by using strategies of “gain-of-function” and ”lose-of-function” and adipose tissue specific knockout cell and mouse models, we aim to investigate the role and mechanism of DDIT4 in the regulation of adipose browning and thermogenesis, and to explore DDIT4 mediated molecular networks that are involved in β-adrenergic signaling and mTORC1 related pathways. The project will help to identify a novel energy sensor and molecule network that is important for thermogenesis and regulation of glucose and lipid metabolism.