Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPβ. Conditionally deleting the essential mTORC2 subunit Rictor in mature adipocytes decreases ChREBPβ expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity. Mechanistically, Rictor/mTORC2 promotes ChREBPβ expression in part by controlling glucose uptake, but without impairing pan-AKT signalling. High-fat diet also rapidly decreases adipose tissue ChREBPβ expression and insulin sensitivity in wild-type mice, and does not further exacerbate insulin resistance in adipose tissue Rictor knockout mice, implicating adipose tissue DNL as an early target in diet-induced insulin resistance. These data suggest mTORC2 functions in WAT as part of an extra-hepatic nutrient-sensing mechanism to control glucose homeostasis.

中文翻译：

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脂肪组织mTORC2调节ChREBP驱动的新生脂肪生成和肝糖代谢。

新生脂肪组织（DNL）对胰岛素敏感性产生积极影响，肥胖症减少，并预测胰岛素抵抗。因此，阐明控制脂肪组织DNL的机制可能会导致2型糖尿病的治疗。在这里，我们报告说，雷帕霉素复合物2（mTORC2）的机械目标在白色脂肪组织（WAT）中起作用，以控制脂生性转录因子ChREBPβ的表达。有条件地删除成熟脂肪细胞中的必需mTORC2亚基Rictor会降低ChREBPβ表达，从而降低WAT中的DNL，并损害肝胰岛素敏感性。从机制上讲，Rictor / mTORC2部分地通过控制葡萄糖摄取来促进ChREBPβ表达，但不损害pan-AKT信号传导。高脂饮食还可以迅速降低野生型小鼠的脂肪组织ChREBPβ表达和胰岛素敏感性，并且不会进一步加剧肥胖组织Rictor基因敲除小鼠的胰岛素抵抗，暗示脂肪组织DNL是饮食诱导的胰岛素抵抗的早期靶点。这些数据表明，mTORC2在WAT中发挥功能，是控制葡萄糖稳态的肝外营养传感机制的一部分。