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

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS BROWN FAT ATP-CITRATE LYASE LINKS

CARBOHYDRATE AVAILABILITY TO THERMOGENESIS AND GUARDS AGAINST METABOLIC STRESS Article 14 October 2024 STK3/STK4 SIGNALLING IN ADIPOCYTES REGULATES MITOPHAGY AND ENERGY EXPENDITURE Article

23 March 2021 A CRITICAL ASSESSMENT OF THE ROLE OF CREATINE IN BROWN ADIPOSE TISSUE THERMOGENESIS Article 09 January 2023 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. AUTHOR INFORMATION Author notes * These authors contributed equally: Anita Reddy, Sally Winther. AUTHORS AND AFFILIATIONS *

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Anita Reddy, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski 

& Edward T. Chouchani * Department of Cell Biology, Harvard Medical School, Boston, MA, USA Anita Reddy, Haopeng Xiao, Josefine Jakob, Martha Ordonez & Edward T. Chouchani * Novo

Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark Sally Winther * Department of Cancer Immunology

and Virology, Dana-Farber Cancer Institute, Boston, MA, USA Nhien Tran & Evanna L. Mills * Department of Immunology, Harvard Medical School, Boston, MA, USA Nhien Tran & Evanna L.

Mills * Brain Science Institute, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA Jeffrey D. Rothstein Authors * Anita Reddy View author publications You can also search

for this author inPubMed Google Scholar * Sally Winther View author publications You can also search for this author inPubMed Google Scholar * Nhien Tran View author publications You can

also search for this author inPubMed Google Scholar * Haopeng Xiao View author publications You can also search for this author inPubMed Google Scholar * Josefine Jakob View author

publications You can also search for this author inPubMed Google Scholar * Ryan Garrity View author publications You can also search for this author inPubMed Google Scholar * Arianne Smith

View author publications You can also search for this author inPubMed Google Scholar * Martha Ordonez View author publications You can also search for this author inPubMed Google Scholar *

Dina Laznik-Bogoslavski View author publications You can also search for this author inPubMed Google Scholar * Jeffrey D. Rothstein View author publications You can also search for this

author inPubMed Google Scholar * Evanna L. Mills View author publications You can also search for this author inPubMed Google Scholar * Edward T. Chouchani View author publications You can

also search for this author inPubMed Google Scholar CONTRIBUTIONS 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.

CORRESPONDING AUTHOR Correspondence to Edward T. Chouchani. ETHICS DECLARATIONS COMPETING INTERESTS E.T.C. is scientific founder and equity holder in Matchpoint Therapeutics and Aevum

Therapeutics. All other authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _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.

ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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 REPORTING SUMMARY 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. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a

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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 Download citation

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