title: Pharmacological and Genetic Manipulation of p53 in Brown Fat at Adult But Not Embryonic Stages Regulates Thermogenesis and Body Weight in Male Mice.
abstract: p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. However, its metabolic role in brown adipose tissue (BAT) remains largely unknown. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. To this end, we generated and characterized global p53-null mice and mice lacking p53 specifically in BAT. Additionally we performed gain-and-loss-of-function experiments in the BAT of adult mice using virogenetic and pharmacological approaches. BAT was collected and analyzed by immunohistochemistry, thermography, real-time PCR, and Western blot. p53-deficient mice were resistant to diet-induced obesity due to increased energy expenditure and BAT activity. However, the deletion of p53 in BAT using a Myf5-Cre driven p53 knockout did not show any changes in body weight or the expression of thermogenic markers. The acute inhibition of p53 in the BAT of adult mice slightly increased body weight and inhibited BAT thermogenesis, whereas its overexpression in the BAT of diet-induced obese mice reduced body weight and increased thermogenesis. On the other hand, pharmacological activation of p53 improves body weight gain due to increased BAT thermogenesis by sympathetic nervous system in obese adult wild-type mice but not in p53(-/-) animals. These results reveal that p53 regulates BAT metabolism by coordinating body weight and thermogenesis, but these metabolic actions are tissue specific and also dependent on the developmental stage.
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Omar
authors.initials: O
authors.lastname: Al-Massadi
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Begoña
authors.initials: B
authors.lastname: Porteiro
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Kuhlow
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Köhler
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: María J
authors.initials: MJ
authors.lastname: Gonzalez-Rellan
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Lavandeira
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Díaz-Rodríguez
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Mar
authors.initials: M
authors.lastname: Quiñones
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Senra
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Clara V
authors.initials: CV
authors.lastname: Alvarez
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Schulz
authors.affiliation: Department of Physiology (O.A.-M., B.P., M.J.G.-R., M.G.-L., E.D.R., M.Q., A.S., C.V.A., M.L., C.D., R.N.), Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (O.A.-M., B.P., M.J.G.-R., M.Q., M.L., C.D., R.N.), Santiago de Compostela 15706, Spain; Department of Adipocyte Development and Nutrition (D.K., M.K., T.J.S.), German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany; and German Center for Diabetes Research (T.J.S.), München-Neuherberg 85764, Germany.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D052683:Somatotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D022722:Thermogenesis / Q000187:drug effects* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin