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.
Originalsprog | Engelsk |
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Tidsskrift | Nature Metabolism |
Vol/bind | 6 |
Udgave nummer | 3 |
Sider (fra-til) | 567–577 |
Antal sider | 11 |
ISSN | 2522-5812 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information: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.
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.