PT  - JOURNAL ARTICLE
AU  - Anita Reddy
AU  - Sally Winther
AU  - Nhien Tran
AU  - Haopeng Xiao
AU  - Josefine Jakob
AU  - Ryan Garrity
AU  - Arianne Smith
AU  - Evanna L. Mills
AU  - Edward T. Chouchani
TI  - Monocarboxylate transporters facilitate succinate uptake into brown adipocytes
AID  - 10.1101/2023.03.01.530625
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.01.530625
4099  - http://biorxiv.org/content/early/2023/03/02/2023.03.01.530625.short
4100  - http://biorxiv.org/content/early/2023/03/02/2023.03.01.530625.full
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 of it 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, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacity in vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.Competing Interest StatementE.T.C. is a founder, board member and equity holder in Matchpoint Therapeutics and Aevum Therapeutics.