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Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure
Katja Drägert1, Indranil Bhattacharya1, Giovanni Pellegrini1
1From the Research Unit, Department of Internal Medicine (K.D., I.B., S.G., R.H, E.B., E.H.) and Division of Surgical Research (M.A.), University Hospital Zurich, Zurich, Switzerland; Center of Competence Multimorbidity and University Research Priority Program "Dynamics of Healthy Aging" (K.D., I.B., S.G., R.H, E.B., E.H.), Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse faculty (G.P.), Zurich Integrative Rodent Physiology (P.S.), Institute of Pharmacology and Toxicology (A.A., S.A.B.), Horten Center for Patient-Oriented Research and Knowledge Transfer (U.H.), Cardioimmunology, Center of Molecular Cardiology (P.B.), and Zurich Center for Integrative Human Physiology (E.B.), University of Zurich, Zurich, Switzerland; and Biozentrum, University of Basel, Basel, Switzerland (M.N.H.).
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.
Insights
The mammalian target of rapamycin complex 2 (mTORC2) protein RICTOR is crucial for blood pressure regulation. Its absence in mice elevates blood pressure and disrupts normal physiological rhythms.
Area of Science:
- Physiology
- Molecular Biology
- Cardiovascular Science
Background:
- Mammalian target of rapamycin complex 2 (mTORC2) is activated by growth factors and plays roles in metabolism and vascular function.
- Perivascular adipose tissue mTORC2 regulates vascular reactivity by controlling inflammatory molecules.
- The role of RICTOR/mTORC2 in blood pressure regulation remains unclear.
Purpose of the Study:
- To investigate the contribution of RICTOR/mTORC2 to blood pressure regulation.
- To determine the physiological consequences of Rictor deletion in adipocytes.
Main Methods:
- Radiotelemetry was used to measure blood pressure and heart rate in control and Rictor knockout (Rictor(aP2KO)) mice.
- Gene expression analysis was performed on adipose tissue and cardiac tissue.
- Clock gene expression was assessed in perivascular adipose tissue and the suprachiasmatic nucleus.
Main Results:
- Rictor(aP2KO) mice exhibited increased mean arterial pressure and impaired nocturnal blood pressure decline.
- Elevated heart rate and locomotor activity were observed during the dark period in Rictor(aP2KO) mice.
- Cardiomyocyte hypertrophy, decreased natriuretic peptide expression, and altered clock gene expression in perivascular adipose tissue were noted.
Conclusions:
- RICTOR/mTORC2 signaling in adipocytes is essential for normal blood pressure regulation.
- The study highlights the critical role of RICTOR/mTORC2 in integrating vascular, adipocyte, and brain signals for physiological homeostasis.
- Disruption of RICTOR/mTORC2 impacts blood pressure, cardiac function, and circadian rhythms.
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