Abstract
Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
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Data availability
Mass spectrometry proteomics data have been deposited to ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048056. All other data are available from the corresponding author upon request.
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Acknowledgements
This work was supported by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research centre, based at the University of Copenhagen, and partially funded by an unconditional donation from the Novo Nordisk Foundation (grant number NNF18CC0034900), a fellowship from the Novo Nordisk Foundation (NNF18OC0032380) (S.W.), the Claudia Adams Barr Program (E.T.C.), the Lavine Family Fund (E.T.C.), the Pew Charitable Trust (E.T.C.), NIH DK123095 (E.T.C.), NIH AG071966 (E.T.C.), The Smith Family Foundation (E.T.C.) and the American Federation for Aging Research (E.T.C.). We would also like to acknowledge the Nikon Imaging Center at Harvard Medical School for their help with the pH imaging experiments and the Tseng Laboratory for the human brown adipocyte cell line.
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A.R. and E.T.C. wrote the manuscript. S.W. conducted and designed all [14C4]-succinate experiments. E.L.M., R.G. and S.W. performed the in vivo tracing experiment following acute MCT inhibition using AZD3965. A.R., N.T., D.L.-B. and E.L.M. conducted in vivo tracing experiment in MCT1 KO mice. H.X. performed proteomics to confirm MCT1 KO using BAT collected from MCT1 KO mice. J.J. and R.G. conducted in vitro [13C4]-succinate tracing experiments following treatment with AZD3965. E.L.M., R.G. and M.O. performed the in vitro [13C4]-succinate dose curve tracing experiment. A.R. performed imaging experiments to determine cytosolic pH. J.D.R. generated MCT1 KO mice. A.R. and A.S. performed the in vitro [13C4]-succinate tracing experiment, while N.E., E.T.C, S.W., E.L.M. and A.R. oversaw the experiments and data analysis. All authors edited the manuscript.
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E.T.C. is scientific founder and equity holder in Matchpoint Therapeutics and Aevum Therapeutics. All other authors declare no competing interests.
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Nature Metabolism thanks Zachary Gerhart-Hines, Giulio Superti-Furga and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Giménez-Cassina, in collaboration with the Nature Metabolism team.
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Extended data
Extended Data Fig. 1 Candidate transporters identified from comparative screen.
a. Slc26a2 and Slc26a6 were genetically depleted in brown adipocytes. Knockdown was confirmed by qPCR> Cells were then treated with 14C4-succinate and transport was monitored (n = 3). b. qPCR data confirming knockdown of MCTs from Fig. 2f (n = 3).
Supplementary information
Supplementary Table 1
List of solute carriers identified across four proteomics and RNA sequencing datasets. Proteins that are enriched in BAT compared with WAT are indicated. Proteins highlighted in bold are candidate succinate transporters.
Supplementary Table 2
Relative protein abundance in MCT1 KO mice compared with WT mice.
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Reddy, A., Winther, S., Tran, N. et al. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes. Nat Metab 6, 567–577 (2024). https://doi.org/10.1038/s42255-024-00981-5
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DOI: https://doi.org/10.1038/s42255-024-00981-5
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