mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
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DOI：
10.1038/s41467-020-14430-w
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发表时间：
2020-01-29
影响因子：
16.6
通讯作者：
Guertin, D. A.
中科院分区：
文献类型：
--
作者：
Calejman, C. Martinez;Trefely, S.;Guertin, D. A.
mTORC 2在疏水基序位点磷酸化AKT，其是胰岛素敏感性的生物标志物。在棕色脂肪细胞中，mTORC 2调节葡萄糖和脂质代谢，但其机制尚不清楚，因为下游AKT信号转导似乎不受mTORC 2损失的影响。在这里，通过应用免疫印迹，有针对性的磷酸蛋白质组学和代谢产物分析，我们确定ATP-柠檬酸裂解酶（ACLY）作为一个明显的mTORC 2敏感的AKT底物在棕色前脂肪细胞。mTORC 2对于大多数其他检查的AKT作用似乎是不稳定的，表明mTORC 2-AKT信号传导中先前未被认识到的选择性。拯救实验表明，棕色前脂肪细胞需要mTORC 2/AKT/ACLY途径来诱导PPAR-gamma并在分化期间建立表观遗传景观。成熟棕色脂肪细胞中的证据也表明mTORC 2通过ACLY起作用，以增加碳水化合物反应元件结合蛋白（ChREBP）活性、组蛋白乙酰化和葡萄糖-脂肪生成基因表达。底物利用研究还表明mT 0 RC 2通过乙酰辅酶A合成酶2（ACSS 2）促进从乙酸合成乙酰辅酶A。这些数据表明，mTORC 2的主要作用是控制核质乙酰辅酶A的合成。
mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetylCoA synthesis.