Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to regulating glucose and lipid metabolism. In the perivascular adipose tissue (PVAT) mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (RictoraP2KO) mice generated by using adipocyte protein-2 gene promoter-driven CRE recombinase to delete Rictor. 24 hour mean arterial pressure (MAP) was increased in RictoraP2KO mice, and the physiologic decline in MAP during the dark period impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides (NPs) and NP receptor expression in adipocytes. Moreover, clock gene expression was dampened or phase-shifted in PVAT. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus (SCN), though Rictor gene expression was also lower in brain of RictoraP2KO mice. Thus, the present study underscores the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes and brain to tune physiological outcomes such as blood pressure and locomotion. Gene expression in PVAT of RictoraP2KO mice was compared to controls (Rictorfl/fl) mice.雷帕霉素靶蛋白复合物2（mammalian target of rapamycin complex 2, mTORC2）含有必需蛋白RICTOR，可被生长因子激活。脂肪组织中的mTORC2参与调控糖脂代谢。血管周围脂肪组织（perivascular adipose tissue, PVAT）内的mTORC2通过调控炎症分子的表达，维持正常的血管反应性。为评估RICTOR/mTORC2是否参与血压调控，我们采用无线电遥测方法，对对照组小鼠以及利用脂肪细胞蛋白2基因启动子驱动的CRE重组酶敲除Rictor以制备Rictor脂肪组织特异性敲除（RictoraP2KO）小鼠开展实验。结果显示，RictoraP2KO小鼠的24小时平均动脉压（mean arterial pressure, MAP）升高，且黑暗时段MAP的生理性下降受到损害。与此同时，黑暗时段的心率与运动活性升高，其变化模式与血压改变一致。该表型伴随轻度心肌细胞肥大，以及脂肪细胞中心脏钠尿肽（natriuretic peptides, NPs）及其受体表达的下调。此外，血管周围脂肪组织中的生物钟基因表达受到抑制或发生时相偏移。在主生物钟视交叉上核（suprachiasmatic nucleus, SCN）中未观察到生物钟基因表达的差异，尽管RictoraP2KO小鼠大脑内的Rictor基因表达同样降低。综上，本研究凸显了RICTOR/mTORC2在血管、脂肪细胞与大脑之间的相互调控中发挥的重要作用，可调节血压、运动活性等生理结局。本研究将RictoraP2KO小鼠的血管周围脂肪组织基因表达与对照组（Rictorfl/fl）小鼠进行了对比。