Wang, D.; Li, M.; Lu, T.; Matsushita, M.; Sakai, J.; Saito, M.; Yoneshiro, T.; Kajimura, S.

Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less defined. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a role for BAT in the clearance of circulating branched-chain amino acids and triglycerides, and also identify a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species (ROS) production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.