mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes.
mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes.
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DOI：
10.1007/s11745-010-3488-y
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发表时间：
2010-12
期刊：
影响因子：
1.9
通讯作者：
Fingar DC
中科院分区：
文献类型：
--
作者：
Soliman GA;Acosta-Jaquez HA;Fingar DC
mTOR复合物1（mTORC 1）的信号传导促进响应生长因子，营养素和激素信号的合成代谢细胞过程。许多临床试验采用mTORC 1抑制剂雷帕霉素（又名西罗莫司）来抑制器官移植后的患者的免疫，已经记录了高甘油三酯血症和血清游离脂肪酸（FFA）升高的发展。因此，我们使用培养的小鼠3 T3-L1脂肪细胞研究了mTORC 1在控制三酰甘油（TAG）代谢中的细胞作用。我们发现，用雷帕霉素处理脂肪细胞使胰岛素刺激的TAG储存减少约50%。为了确定雷帕霉素是否通过上调脂解速率来减少TAG储存，我们在不存在和存在雷帕霉素和异丙肾上腺素的情况下处理脂肪细胞，异丙肾上腺素是一种β2-肾上腺素能激动剂，其激活cAMP/蛋白激酶A（PKA）途径以促进脂解。我们发现，雷帕霉素增强异丙肾上腺素诱导的脂解，而不改变cAMP水平。雷帕霉素增强了异丙肾上腺素刺激的激素敏感脂肪酶（HSL）在丝氨酸-563（PKA位点）上的磷酸化，但对HSL S565（AMPK位点）的磷酸化没有影响。此外，雷帕霉素不影响异丙肾上腺素介导的围脂蛋白磷酸化，围脂蛋白是一种包被脂滴的蛋白质，在PKA磷酸化后启动脂解。这些数据表明，mTORC 1信号传导的抑制与β-肾上腺素能-cAMP/PKA途径协同作用，以增加HSL的磷酸化，从而促进脂肪酸诱导的脂解。此外，它们揭示了mTORC 1的新代谢功能; mTORC 1信号转导抑制脂解，从而增加TAG储存。
Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immuno-suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3-L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulin-stimulated TAG storage ~50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2-adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenol-induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenol-stimulated phosphorylation of hormone sensitive lipase (HSL) on Ser-563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenol-mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the β-adrenergic-cAMP/PKA pathway to augment phosphorylation of HSL to promote hormone-induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage.
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