Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease.
Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease.
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DOI：
10.1016/j.celrep.2014.06.007
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发表时间：
2014-07-10
期刊：
影响因子：
8.8
通讯作者：
Guertin DA
中科院分区：
文献类型：
--
作者：
Hung CM;Calejman CM;Sanchez-Gurmaches J;Li H;Clish CB;Hettmer S;Wagers AJ;Guertin DA
MTORC2的体内功能以及控制棕色脂肪组织(BAT)燃料利用和活性的信号机制尚不清楚。在这里，通过有条件地删除Rictorin的Myf5谱系，我们在体内提供了证据，证明mTORC2对于骨骼肌的发育和再生是必不可少的，但对蝙蝠的生长是必不可少的。此外，删除RictorinMyf5前体会将BAT代谢转移到氧化程度更高、脂肪生成更少的状态，并保护小鼠在体温中和温度下免受肥胖和代谢性疾病的影响。此外，我们还发现RICTOR是棕色脂肪细胞在体外分化所必需的，该机制特异性地需要AKT1疏水基序的磷酸化，但不依赖于PAN-AKT信号，并被BMP7拯救。我们的发现为调节棕色脂肪细胞的信号回路提供了新的见解，并可能对开发旨在增加能量消耗的疗法作为对抗人类肥胖的手段具有重要意义。
The in vivo functions of mTORC2, and the signaling mechanisms that control brown adipose tissue (BAT) fuel utilization and activity, are not well understood. Here, by conditionally deleting Rictorin the Myf5-lineage, we provide in vivo evidence that mTORC2 is dispensable for skeletal muscle development and regeneration but essential for BAT growth. Furthermore, deleting RictorinMyf5 precursors shifts BAT metabolism to a more oxidative and less lipogenic state and protects mice from obesity and metabolic disease at thermoneutrality. We additionally find that Rictor is required for brown adipocyte differentiation in vitro, that the mechanismspecifically requires AKT1 hydrophobic motif phosphorylation but is independent of pan-AKT signaling, and is rescued with BMP7. Our findings provide new insights into the signaling circuitry that regulates brown adipocytes and could have important implications for developing therapies aimed at increasing energy expenditure as a means to combat human obesity.
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