Objective

Pharmacological agents targeting the mTOR complexes are used clinically as immunosuppressants and anticancer agents and can extend the lifespan of model organisms. An undesirable side effect of these drugs is hyperlipidemia. Although multiple roles have been described for mTOR complex 1 (mTORC1) in lipid metabolism, the etiology of hyperlipidemia remains incompletely understood. The objective of this study was to determine the influence of adipocyte mTORC1 signaling in systemic lipid homeostasis in vivo.

Methods

We characterized systemic lipid metabolism in mice lacking the mTORC1 subunit Raptor (Raptor^aKO), the key lipolytic enzyme ATGL (ATGL^aKO), or both (ATGL-Raptor^aKO) in their adipocytes.

Results

Mice lacking mTORC1 activity in their adipocytes failed to completely suppress lipolysis in the fed state and displayed prominent hypertriglyceridemia and hypercholesterolemia. Blocking lipolysis in their adipose tissue restored normal levels of triglycerides and cholesterol in the fed state as well as the ability to clear triglycerides in an oral fat tolerance test.

Conclusions

Unsuppressed adipose lipolysis in the fed state interferes with triglyceride clearance and contributes to hyperlipidemia. Adipose tissue mTORC1 activity is necessary for appropriate suppression of lipolysis and for the maintenance of systemic lipid homeostasis.

中文翻译：

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mTORC1抑制脂肪细胞的脂解作用，以预防系统性高脂血症。

客观的

针对mTOR复合物的药物在临床上被用作免疫抑制剂和抗癌剂，并且可以延长模型生物的寿命。这些药物的不良副作用是高脂血症。尽管已在脂质代谢中描述了mTOR复合物1（mTORC1）的多种作用，但对高脂血症的病因学仍不完全了解。这项研究的目的是确定体内脂肪细胞mTORC1信号传导对系统性脂质稳态的影响。

方法

我们表征了小鼠脂肪细胞中缺少mTORC1亚单位Raptor（Raptor ^aKO），关键脂解酶ATGL（ATGL ^aKO）或两者（ATGL-Raptor ^aKO）的小鼠的全身脂质代谢。

结果

在它们的脂肪细胞中缺乏mTORC1活性的小鼠在进食状态下不能完全抑制脂解，并表现出明显的高甘油三酯血症和高胆固醇血症。阻断脂肪组织中的脂解可以恢复进食状态下的甘油三酸酯和胆固醇的正常水平，以及在口服脂肪耐受性测试中清除甘油三酸酯的能力。

结论

在进食状态下未抑制的脂肪脂解会干扰甘油三酸酯的清除并导致高脂血症。脂肪组织mTORC1活性对于适当抑制脂解和维持全身脂质稳态是必需的。