Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity.
Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity.
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DOI：
10.1016/j.molmet.2015.11.005
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发表时间：
2016-02
影响因子：
8.1
通讯作者：
Laplante M
中科院分区：
文献类型：
--
作者：
Caron A;Labbé SM;Lanfray D;Blanchard PG;Villot R;Roy C;Sabatini DM;Richard D;Laplante M
雷帕霉素（mTOR）的机制靶标是丝氨酸-苏氨酸激酶，其功能为调节能量稳态的不同蛋白质复合物（mTORC 1和mTORC 2）。DEP-domain containing mTOR-interacting protein（DEPTOR）是这些复合物的一部分，并且已知其抑制mTORC 1功能，从而在几种模型中减少mTORC 1负反馈并促进胰岛素信号传导和Akt/PKB活化。最近，我们观察到DEPTOR在大脑的几个结构中表达，包括内侧基底下丘脑（MBH），这是一个调节能量平衡的区域。MBH中的DEPTOR是否在调节能量平衡和下丘脑胰岛素信号传导中起功能性作用从未被测试过。我们已经产生了一种新的条件性转基因小鼠模型的基础上Cre-LoxP系统，允许有针对性的过度表达DEPTOR。对MBH中过表达DEPTOR的小鼠进行代谢表型分析，并评估MBH胰岛素信号传导。我们首次报道了DEPTOR的系统性（脑和外周）过表达可预防高脂饮食诱导的肥胖，改善葡萄糖代谢并防止肝脂肪变性。这些表型与摄食量和饲料效率的降低以及耗氧量的升高有关。引人注目的是，MBH中DEPTOR的特异性过表达完全概括了这些表型。DEPTOR过表达与下丘脑胰岛素信号传导增加相关，如Akt/PKB活化升高所示。总之，这些结果支持MBH DEPTOR在调节能量平衡和代谢中的作用。DEPTOR的系统性（脑和外周）过表达促进活性并改善葡萄糖稳态。DEPTOR的系统性（脑和外周）过表达可防止高脂饮食诱导的肥胖和代谢改变。Deptor在小鼠脑中广泛表达，在调节能量平衡的大脑关键区域--中基底下丘脑（MBH）中有高表达。MBH特异性DEPTOR过表达改善葡萄糖代谢并保护小鼠免受肥胖。MBH特异性DEPTOR过表达促进下丘脑Akt/PKB信号传导
The mechanistic target of rapamycin (mTOR) is a serine–threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulate energy homeostasis. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to dampen mTORC1 function, consequently reducing mTORC1 negative feedbacks and promoting insulin signaling and Akt/PKB activation in several models. Recently, we observed that DEPTOR is expressed in several structures of the brain including the mediobasal hypothalamus (MBH), a region that regulates energy balance. Whether DEPTOR in the MBH plays a functional role in regulating energy balance and hypothalamic insulin signaling has never been tested. We have generated a novel conditional transgenic mouse model based on the Cre-LoxP system allowing targeted overexpression of DEPTOR. Mice overexpressing DEPTOR in the MBH were subjected to a metabolic phenotyping and MBH insulin signaling was evaluated. We first report that systemic (brain and periphery) overexpression of DEPTOR prevents high-fat diet-induced obesity, improves glucose metabolism and protects against hepatic steatosis. These phenotypes were associated with a reduction in food intake and feed efficiency and an elevation in oxygen consumption. Strikingly, specific overexpression of DEPTOR in the MBH completely recapitulated these phenotypes. DEPTOR overexpression was associated with an increase in hypothalamic insulin signaling, as illustrated by elevated Akt/PKB activation. Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism. Systemic (brain and peripheral) overexpression of DEPTOR promotes activity and improves glucose homeostasis. Systemic (brain and peripheral) overexpression of DEPTOR protects againts high-fat diet-induced obesity and metabolic alterations. Deptor is widely expressed in the mouse brain, with a high expression in the mediobasal hypothalamus (MBH), a key region of the brain that regulates energy balance. MBH-specific DEPTOR overexpression improves glucose metabolism and protects mice against obesity. MBH-specific DEPTOR overexpression promotes hypothalamic Akt/PKB signaling.