Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

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 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 capacityin vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

Brown fat thermogenesis and branched-chain amino acids in metabolic disease

“…Now, the apparent fact that BAT recruits circulating metabolites beyond the historically recognized substrates for thermogenesis is increasingly being recognized. For example, recent reports posit a role for succinate, a TCA intermediate, wherein uptake or accumulation of succinate drives thermogenesis through its oxidation and generation of reactive oxygen species [14,15]. Moreover, several studies have now also shown that SNS stimulation strongly activates BAT thermogenesis and decreases the levels of circulating branched-chain amino acids (BCAAs), leucine (Leu), isoleucine (Ile), and valine (Val) [16][17][18].…”