title: Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure.
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.
authors.affiliation: From 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.).
authors.forename: Katja
authors.initials: K
authors.lastname: Drägert
authors.affiliation: From 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.).
authors.forename: Indranil
authors.initials: I
authors.lastname: Bhattacharya
authors.affiliation: From 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.).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pellegrini
authors.affiliation: From 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.).
authors.forename: Petra
authors.initials: P
authors.lastname: Seebeck
authors.affiliation: From 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.).
authors.forename: Abdelhalim
authors.initials: A
authors.lastname: Azzi
authors.affiliation: From 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.).
authors.forename: Steven A
authors.initials: SA
authors.lastname: Brown
authors.affiliation: From 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.).
authors.forename: Stavroula
authors.initials: S
authors.lastname: Georgiopoulou
authors.affiliation: From 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.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Held
authors.affiliation: From 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.).
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
authors.affiliation: From 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.).
authors.forename: Margarete
authors.initials: M
authors.lastname: Arras
authors.affiliation: From 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.).
authors.forename: Rok
authors.initials: R
authors.lastname: Humar
authors.affiliation: From 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.).
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: From 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.).
authors.forename: Edouard
authors.initials: E
authors.lastname: Battegay
authors.affiliation: From 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.). Elvira.haas@usz.ch.
authors.forename: Elvira
authors.initials: E
authors.lastname: Haas
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D006339:Heart Rate / Q000502:physiology; D006984:Hypertrophy; D007328:Insulin / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009043:Motor Activity / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: RICTOR, mouse; adipose tissue; arterial pressure; circadian clocks; locomotor activity; mTOR complex 2