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

Chul-Hong Park; Minsung Park; Miranda E Kelly; Helia Cheng; Sang Ryeul Lee; Cholsoon Jang; Ji Suk Chang

doi:10.1016/j.celrep.2025.115888

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

Cell Rep. 2025 Jun 19;44(7):115888. doi: 10.1016/j.celrep.2025.115888. Online ahead of print.

Authors

Chul-Hong Park¹, Minsung Park¹, Miranda E Kelly², Helia Cheng¹, Sang Ryeul Lee³, Cholsoon Jang², Ji Suk Chang⁴

Affiliations

¹ Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
² Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
³ Transgenics Core, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
⁴ Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Electronic address: jisuk.chang@pbrc.edu.

PMID: 40540398
DOI: 10.1016/j.celrep.2025.115888

Abstract

Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs 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 FAs under cold conditions.

Keywords: CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis.