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


Drägert, Katja; Bhattacharya, Indranil; Pellegrini, Giovanni; Seebeck, Petra; Azzi, Abdelhalim; Brown, Steven A; Georgiopoulou, Stavroula; Held, Ulrike; Blyszczuk, Przemyslaw; Arras, Margarete; Humar, Rok; Hall, Michael N; Battegay, Edouard; Haas, Elvira (2015). Deletion of rictor in brain and fat alters peripheral clock gene expression and increases blood pressure. Hypertension, 66:332-339.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology

04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Pathology
04 Faculty of Medicine > Center of Competence Multimorbidity
08 University Research Priority Programs > Dynamics of Healthy Aging
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:22 June 2015
Deposited On:16 Jul 2015 09:08
Last Modified:21 Nov 2017 17:57
Publisher:Lippincott Williams & Wilkins
ISSN:0194-911X
Additional Information:This is a non-final version of an article published in final form in Drägert et al: Deletion of Rictor in Brain and Fat Alters Peripheral Clock Gene Expression and Increases Blood Pressure, Hypertension, 2015, 66, 332-339.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1161/HYPERTENSIONAHA.115.05398
PubMed ID:26101345

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