Loss of hepatic DEPTOR alters the metabolic transition to fasting.
Loss of hepatic DEPTOR alters the metabolic transition to fasting.
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DOI：
10.1016/j.molmet.2017.02.005
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发表时间：
2017-05
影响因子：
8.1
通讯作者：
Laplante M
中科院分区：
文献类型：
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作者：
Caron A;Mouchiroud M;Gautier N;Labbé SM;Villot R;Turcotte L;Secco B;Lamoureux G;Shum M;Gélinas Y;Marette A;Richard D;Sabatini DM;Laplante M
雷帕霉素（mTOR）的机制靶点是丝氨酸/苏氨酸激酶，其功能为调节生长和代谢的不同蛋白质复合物（mTORC 1和mTORC 2）。含DEP结构域的mTOR相互作用蛋白（DEPTOR）是这些复合物的一部分，已知会降低其活性。DEPTOR缺失是否影响体内代谢和生物体生长从未被测试过。我们已经产生了条件转基因小鼠允许DEPTOR的组织特异性缺失。将该模型与CMV-cre小鼠或白蛋白-cre小鼠杂交以产生全身或肝脏特异性DEPTOR敲除（KO）小鼠。全身DEPTOR KO小鼠存活、可生育、大小正常，并且未显示任何大体身体和代谢异常。为了避免与DEPTOR的早期和全身性损失相关的可能的补偿机制，我们已经删除了肝脏中的DEPTOR，肝脏是一种表达DEPTOR蛋白并响应mTOR激活而受到影响的组织。与对照小鼠相比，肝脏特异性DEPTOR无效小鼠在禁食后显示循环葡萄糖减少。这种效应与肝脏再生潜能的变化无关，但与胰岛素耐量试验期间循环葡萄糖的持续降低有关。除了肝脏特异性DEPTOR KO小鼠的肝糖原含量减少外，禁食时肝脏特异性DEPTOR KO小鼠的肝糖原含量也减少。我们表明，DEPTOR细胞自主性的丧失增加了肝细胞的氧化代谢，这种效应与细胞色素c表达的增加有关，但与线粒体含量或控制氧化代谢的基因表达的变化无关。我们发现，肝脏特异性DEPTOR KO小鼠在禁食时表现出持续的mTORC 1激活，并且用雷帕霉素急性治疗足以使这些小鼠的食欲正常化。我们提出了一个模型，其中肝DEPTOR在过渡到禁食以调整代谢以适应营养状态期间加速mTORC 1的抑制。全身DEPTOR KO小鼠存活，未显示异常。肝脏特异性DEPTOR KO小鼠在禁食时血糖降低。DEPTOR的缺失促进mTORC 1并增加氧化代谢。雷帕霉素纠正肝脏特异性DEPTOR KO小鼠的低血糖症
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested. We have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR knockout (KO) mice. Whole-body DEPTOR KO mice are viable, fertile, normal in size, and do not display any gross physical and metabolic abnormalities. To circumvent possible compensatory mechanisms linked to the early and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a tissue in which DEPTOR protein is expressed and affected in response to mTOR activation. Liver-specific DEPTOR null mice showed a reduction in circulating glucose upon fasting versus control mice. This effect was not associated with change in hepatic gluconeogenesis potential but was linked to a sustained reduction in circulating glucose during insulin tolerance tests. In addition to the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously increased oxidative metabolism in hepatocytes, an effect associated with increased cytochrome c expression but independent of changes in mitochondrial content or in the expression of genes controlling oxidative metabolism. We found that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon fasting, and that acute treatment with rapamycin was sufficient to normalize glycemia in these mice. We propose a model in which hepatic DEPTOR accelerates the inhibition of mTORC1 during the transition to fasting to adjust metabolism to the nutritional status. Whole-body DEPTOR KO mice are viable and do not display abnormalities. Liver-specific DEPTOR KO mice are hypoglycemic when fasted. Loss of DEPTOR promotes mTORC1 and increases oxidative metabolism. Rapamycin corrects hypoglycemia in liver-specific DEPTOR KO mice.