Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

doi:10.1016/j.cmet.2018.11.017

. 2019 Apr 2;29(4):901-916.e8.

doi: 10.1016/j.cmet.2018.11.017. Epub 2018 Dec 20.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Miroslav Balaz¹, Anton S Becker², Lucia Balazova¹, Leon Straub¹, Julian Müller³, Gani Gashi⁴, Claudia Irene Maushart⁴, Wenfei Sun¹, Hua Dong¹, Caroline Moser¹, Carla Horvath¹, Vissarion Efthymiou¹, Yael Rachamin¹, Salvatore Modica¹, Caroline Zellweger³, Sara Bacanovic³, Patrik Stefanicka⁵, Lukas Varga⁶, Barbara Ukropcova⁷, Milan Profant⁵, Lennart Opitz⁸, Ez-Zoubir Amri⁹, Murali K Akula¹⁰, Martin Bergo¹¹, Jozef Ukropec¹², Christian Falk¹³, Nicola Zamboni¹⁴, Matthias Johannes Betz¹⁵, Irene A Burger¹⁶, Christian Wolfrum¹⁷

Affiliations

¹ Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland.
² Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland; Institute of Diagnostic and Interventional Radiology, University Hospital of Zürich, Zürich, Switzerland; Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland.
³ Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland.
⁴ Department of Endocrinology, Diabetology, and Metabolism, University Hospital of Basel, Petersgraben 4, Basel 4031, Switzerland.
⁵ Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia.
⁶ Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia; Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
⁷ Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia; Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
⁸ Functional Genomics Center Zürich, ETH Zürich/University of Zürich, Zürich, Switzerland.
⁹ Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France.
¹⁰ Sahlgrenska Cancer Center, Department of Medicine, University of Gothenburg, Gothenburg, Sweden.
¹¹ Sahlgrenska Cancer Center, Department of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
¹² Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
¹³ Department of Medical Data Management, University Hospital of Zürich, Zürich, Switzerland.
¹⁴ Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
¹⁵ Department of Endocrinology, Diabetology, and Metabolism, University Hospital of Basel, Petersgraben 4, Basel 4031, Switzerland. Electronic address: matthias.betz@usb.ch.
¹⁶ Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. Electronic address: irene.burger@usz.ch.
¹⁷ Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland. Electronic address: christian-wolfrum@ethz.ch.

PMID: 30581121
DOI: 10.1016/j.cmet.2018.11.017

Free article

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Miroslav Balaz et al. Cell Metab. 2019.

Free article

. 2019 Apr 2;29(4):901-916.e8.

doi: 10.1016/j.cmet.2018.11.017. Epub 2018 Dec 20.

Authors

Affiliations

¹ Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland.
² Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland; Institute of Diagnostic and Interventional Radiology, University Hospital of Zürich, Zürich, Switzerland; Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland.
³ Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland.
⁴ Department of Endocrinology, Diabetology, and Metabolism, University Hospital of Basel, Petersgraben 4, Basel 4031, Switzerland.
⁵ Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia.
⁶ Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia; Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
⁷ Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia; Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
⁸ Functional Genomics Center Zürich, ETH Zürich/University of Zürich, Zürich, Switzerland.
⁹ Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France.
¹⁰ Sahlgrenska Cancer Center, Department of Medicine, University of Gothenburg, Gothenburg, Sweden.
¹¹ Sahlgrenska Cancer Center, Department of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
¹² Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
¹³ Department of Medical Data Management, University Hospital of Zürich, Zürich, Switzerland.
¹⁴ Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
¹⁵ Department of Endocrinology, Diabetology, and Metabolism, University Hospital of Basel, Petersgraben 4, Basel 4031, Switzerland. Electronic address: matthias.betz@usb.ch.
¹⁶ Department of Nuclear Medicine, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. Electronic address: irene.burger@usz.ch.
¹⁷ Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland. Electronic address: christian-wolfrum@ethz.ch.

PMID: 30581121
DOI: 10.1016/j.cmet.2018.11.017

Abstract

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.

Keywords: adipocyte browning; energy expenditure; mevalonate pathway; protein prenylation; small GTP-binding proteins; statins; uncoupled mitochondrial respiration.

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Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Affiliations

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

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