TY - JOUR
T1 - Monocarboxylate transporters facilitate succinate uptake into brown adipocytes
AU - Reddy, Anita
AU - Winther, Sally
AU - Tran, Nhien
AU - Xiao, Haopeng
AU - Jakob, Josefine
AU - Garrity, Ryan
AU - Smith, Arianne
AU - Ordonez, Martha
AU - Laznik-Bogoslavski, Dina
AU - Rothstein, Jeffrey D.
AU - Mills, Evanna L.
AU - Chouchani, Edward T.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s42255-024-00981-5
DO - 10.1038/s42255-024-00981-5
M3 - Journal article
C2 - 38378996
AN - SCOPUS:85185303247
VL - 6
SP - 567
EP - 577
JO - Nature Metabolism
JF - Nature Metabolism
SN - 2522-5812
IS - 3
ER -