Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure.
The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. 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 functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1α and PPARα pathways but requires 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 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.
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Audrey
A
Carrière
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Yannick
Y
Jeanson
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Sandra
S
Berger-Müller
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Mireille
M
André
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Vanessa
V
Chenouard
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Emmanuelle
E
Arnaud
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Corinne
C
Barreau
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Romy
R
Walther
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France.
Anne
A
Galinier
Faculté de Médecine, Institut de Biologie Valrose CNRS/INSERM/Université Nice Sophia Antipolis, Nice, France.
Brigitte
B
Wdziekonski
Faculté de Médecine, Institut de Biologie Valrose CNRS/INSERM/Université Nice Sophia Antipolis, Nice, France.
Phi
P
Villageois
INSERM, UMR 1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
Katie
K
Louche
Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, Oslo, Norway.
Philippe
P
Collas
INSERM, UMR 1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
Cédric
C
Moro
Faculté de Médecine, Institut de Biologie Valrose CNRS/INSERM/Université Nice Sophia Antipolis, Nice, France.
Christian
C
Dani
Departament de Bioquimica i Biologia Molecular and Institute of Biomedicine, Universitat de Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
Francesc
F
Villarroya
CNRS 5273, UMR STROMALab, Toulouse, France Université de Toulouse, Université Paul Sabatier, UMR 5273, Toulouse, France INSERM U1031, Toulouse, France Etablissement Français du Sang Pyrénées-Méditerranée, Toulouse, France louis.casteilla@inserm.fr.
Louis
L
Casteilla
D052437:Adipocytes, Brown / Q000378:metabolism*; D052438:Adipocytes, White / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D013234:Stem Cells
D047495:PPAR gamma