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

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.

• Authors: Miroslav Balaz, Anton S Becker, Lucia Balazova, Leon Straub, Julian Müller, Gani Gashi, Claudia Irene Maushart, Wenfei Sun, Hua Dong, Caroline Moser, Carla Horvath, Vissarion Efthymiou, Yael Rachamin, Salvatore Modica, Caroline Zellweger, Sara Bacanovic, Patrik Stefanicka, Lukas Varga, Barbara Ukropcova, Milan Profant, Lennart Opitz, Ez-Zoubir Amri, Murali K Akula, Martin Bergo, Jozef Ukropec, Christian Falk, Nicola Zamboni, Matthias Johannes Betz, Irene A Burger, Christian Wolfrum
• Journal: Cell metabolism (Cell Metab) Vol. 29 Issue 4 Pg. 901-916.e8 (04 02 2019) ISSN: 1932-7420 [Electronic] United States
• PMID: 30581121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• UCP1 protein, human
• Ucp1 protein, mouse
• Uncoupling Protein 1
• Mevalonic Acid

Topics

• Adipocytes, Brown (drug effects, metabolism)
• Adolescent
• Adult
• Animals
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Humans
• Male
• Mevalonic Acid (pharmacology)
• Mice
• Mice, Inbred Strains
• Middle Aged
• Protein Prenylation (drug effects)
• Uncoupling Protein 1 (antagonists & inhibitors, metabolism)
• Young Adult