Makki Kassem, Taront Solenne, Molendi-Coste Olivier, Bouchaert Emmanuel, Neve Bernadette, Eury Elodie, Lobbens Stéphane, Labalette Myriam, Duez Hélène, Staels Bart, Dombrowicz David, Froguel Philippe, Wolowczuk Isabelle
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France.
Lille 2 University, Lille, France; European Genomic Institute for Diabetes (EGID), Lille, France; Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1011, Lille Pasteur Institute, Lille, France.
PLoS One. 2014 Apr 7;9(4):e92684. doi: 10.1371/journal.pone.0092684. eCollection 2014.
The "mechanistic target of rapamycin" (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases.
“雷帕霉素作用机制靶点”（mTOR）是从脂肪细胞到免疫细胞等多种细胞类型生长、增殖和/或运动的核心调控因子，从而将代谢与免疫联系起来。mTOR信号在肥胖状态下过度激活，促进炎症和胰岛素抵抗。因此，人们对开发mTOR抑制剂作为肥胖或糖尿病治疗药物有着浓厚兴趣。然而，尽管有大量研究描述了mTOR抑制在啮齿动物模型中的代谢后果，但迄今为止，其对与肥胖相关的免疫变化的影响从未受到质疑。为了解决这个问题，我们使用了高脂饮食（HFD）喂养的小鼠模型，分别给予和不给予雷帕霉素进行药理学mTOR抑制。雷帕霉素每周给药给HFD喂养的C57BL/6小鼠，持续22周。通过葡萄糖和胰岛素耐量试验以及能量消耗的间接量热法测量来确定代谢效应。对血液、脂肪组织和肝脏中的炎症反应和免疫细胞群体进行了表征。同时，在脂肪组织、肌肉和肝脏中测定了两种mTOR复合物（如mTORC1和mTORC2）的活性。我们发现，雷帕霉素治疗的小鼠更瘦了，能量消耗增加，并且对胰岛素抵抗具有保护作用。雷帕霉素这些有益的代谢作用与脂肪组织和肝脏炎症谱的显著变化有关。重要的是，脂肪组织中具有调节功能的免疫细胞如调节性T细胞（Tregs）和骨髓来源的抑制细胞（MDSCs）增加了。这些雷帕霉素引发的代谢和免疫效应是由mTORC1抑制导致的，而mTORC2活性保持完整。综上所述，我们的结果强化了这样一种观念，即控制代谢组织中的免疫调节细胞对于维持适当的代谢状态至关重要，更广泛地说，支持了寻找mTOR信号通路新型药理学抑制剂以预防和/或治疗代谢疾病的必要性。
