Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.

Unlabelled: Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FA) and glucose under cold stress but favors FA as the primary fuel for heat production. It remains unclear how BAT steer fuel preference toward FA over glucose. Here we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FA under cold conditions.

Highlights: is markedly induced by cold in BAT via a β-adrenergic receptor-PKA-PGC-1α axis The increase in cytosolic GOT1 activates the malate-aspartate shuttle (MAS)MAS activation promotes fatty acid oxidation while reducing glucose oxidation Loss of MAS activity in BAT by deletion shifts the fuel preference to glucose.