Deletion of Rictor in Brain and Fat Alters Peripheral Clock Gene Expression and Increases Blood Pressure

Abstract

Abstract-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 the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, 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 (Rictor aP2KO ) mice generated using adipocyte protein-2 gene promoter-driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in Rictor aP2KO mice, and the physiological decline in mean arterial pressure during the dark period was 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, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of Rictor aP2KO mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity. (Hypertension. 2015;66:332-339.

Effects of rapamycin on growth hormone receptor knockout mice

“…However, it seems that many of the negative adverse effects of rapamycin treatment are mediated by inhibition of mTORC2 (5). It has been recently shown that Rictor has positive effects on a variety of functions involved in whole-body homeostasis (6)(7)(8)(9)(10). Although at this time, the role of mTORC2 in the regulation of longevity is uncertain (11), several lines of evidence imply that mTORC2 may have opposite effects on aging compared with mTORC1.…”

Basal mTORC2 activity and expression of its components display diurnal variation in mouse perivascular adipose tissue

“…We therefore speculate that during metabolic diseases such as obesity the diurnal variation of Rictor is dysregulated and perturbs vascular physiology. In line, we have shown that ablation of Rictor in adipose tissue and brain results in impaired PVAT function resembling a phenotype which is similar to metabolic disease and impaired diurnal blood pressure regulation possibly by affecting inflammatory molecule and natriuretic peptide expression [7,19].…”

“…The method was performed essentially as described earlier [7]: RNA from PVAT, EFAT and BAT was extracted using RNeasy ® lipid tissue kit and from thoracic aortas using RNeasy ® fibrous tissue kit, according to the protocol of the manufacturer (Qiagen, Hombrechtikon, Switzerland) respectively. DNA was removed using an on- Each reaction was performed in duplicates using Bio-Rad CFX96 Real-Time System and iQ™ SYBR ® Green Supermix (BioRad, Hercules, CA, USA) and specific mouse primers.…”

“…Adipocyte-specific deficiency of mTORC2 by ablation of Rictor results in higher lean mass due to increased levels of insulin and insulin-like growth factor, enhanced glucose metabolism and insulin resistance in mice [5,6]. Using this mouse model we have recently shown that clock gene expression in perivascular adipose tissue (PVAT) is altered in comparison with tissue derived from control mice [7]. Deletion of Rictor in adipocytes had no effect on aortic tissue consisting mainly of smooth muscle and endothelial cells.…”

mTOR Signaling, Translational Control, and the Circadian Clock

“…In Drosophila , TOR rhythms are also found in the brain and in particular the ventral lateral neurons ( Zheng and Sehgal, 2010 ; Kijak and Pyza, 2017 ). In peripheral tissues, mTOR activities are rhythmic in the liver, cardiac and skeletal muscles, adipocytes, and retinal photoreceptors ( Huang et al, 2013 ; Jouffe et al, 2013 ; Shavlakadze et al, 2013 ; Khapre et al, 2014 ; Drägert et al, 2015a , b ; Lipton et al, 2015 , 2017 ; Chang et al, 2016 ). Interestingly, mTOR also shows circadian rhythms in human osteosarcomas, mouse renal carcinomas as well as human breast cancer cells ( Zhang et al, 2009 , 2018 ; Okazaki et al, 2014 ).…”