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

Balaz, Miroslav and Becker, Anton S. and Balazova, Lucia and Straub, Leon and Müller, Julian and Gashi, Gani and Maushart, Claudia Irene and Sun, Wenfei and Dong, Hua and Moser, Caroline and Horvath, Carla and Efthymiou, Vissarion and Rachamin, Yael and Modica, Salvatore and Zellweger, Caroline and Bacanovic, Sara and Stefanicka, Patrik and Varga, Lukas and Ukropcova, Barbara and Profant, Milan and Opitz, Lennart and Amri, Ez-Zoubir and Akula, Murali K. and Bergo, Martin and Ukropec, Jozef and Falk, Christian and Zamboni, Nicola and Betz, Matthias Johannes and Burger, Irene A. and Wolfrum, Christian. (2019) Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation. Cell Metabolism, 29 (4). pp. 901-916.e8.

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie
UniBasel Contributors:Betz, Matthias Johannes Maximilian
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Oct 2021 15:29
Deposited On:06 Oct 2021 15:29

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