Browning of White Adipose Cells by Intermediate Metabolites:An Adaptive Mechanism to Alleviate Redox Pressure
- Audrey Carrière*,1,2,3,4,
- Yannick Jeanson*,1,2,3,4,
- Sandra Berger-Müller1,2,3,4,
- Mireille André1,2,3,4,
- Vanessa Chenouard1,2,3,4,
- Emmanuelle Arnaud1,2,3,4,
- Corinne Barreau1,2,3,4,
- Romy Walther1,2,3,4,
- Anne Galinier1,2,3,4,
- Brigitte Wdziekonski5,
- Phi Villageois5,
- Katie Louche6,
- Philippe Collas7,
- Cédric Moro6,
- Christian Dani5,
- Francesc Villarroya8 and
- Louis Casteilla1,2,3,4,#
- 1CNRS 5273; UMR STROMALab, F-31 432 Toulouse Cedex 4, France
- 2Université de Toulouse; UPS, UMR5273 F-31 432 Toulouse Cedex 4, France
- 3INSERM U1031 F-31 432 Toulouse Cedex 4, France
- 4EFS Pyrénées –Méditerranée; BP 84225, F-31 432 Toulouse Cedex 4, France
- 5Institut de Biologie Valrose CNRS/INSERM/Université Nice Sophia-Antipolis, Faculté de Médecine 06107 Nice Cedex 2, France
- 6INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
- 7Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway
- 8Departament de Bioquimica I Biologia Molecular, and Institute of Biomedicine (IBUB), Universitat de Barcelona; and CIBER Fisiopatologia de la Obesidad y Nutricion, Av Diagonal 643, 08028 Barcelona, Spain
- #Corresponding author: Louis Casteilla Email:
The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via the uncoupling protein-1 (UCP1). Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of a functional UCP1 protein. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of HIF-1α and PPARα pathways but requires an active PPARγ signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications, as a result of lactate transport through monocarboxylate transporters. Further, the ketone body β-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with uncoupled mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance
* Both authors equally contributed to this work
- Received December 13, 2013.
- Accepted April 22, 2014.
- © 2014 by the American Diabetes Association.
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