Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.

Summary

Multi-omics across BAT-ablated mice and humans revealed that BAT shapes the circulating metabolome, clearing BCAAs and triglycerides and producing a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA). 3-OHSA serves as a readout of BAT activation and directly lowers hepatic mitochondrial membrane potential and ROS, limiting oxidative stress and defining a BAT–liver protective axis.

Key Findings

• Integrated metabolomics/lipidomics across BAT-ablated mice and human cohorts defined BAT-linked circulating molecular signatures.
• BAT activity supports clearance of circulating branched-chain amino acids and triglycerides.
• Identification of a cold-inducible BAT-derived metabolite, 3-hydroxystearic acid (3-OHSA), detectable in circulation.
• 3-OHSA reduces hepatic mitochondrial membrane potential and reactive oxygen species, limiting oxidative stress.

Clinical Implications

3-OHSA could serve as a biomarker of BAT activation and a lead for hepatoprotective therapies targeting oxidative stress. Strategies that augment BAT activity or leverage 3-OHSA biology may complement MASLD and metabolic syndrome management.

Limitations

• Predominantly preclinical; causal relevance and pharmacokinetics of 3-OHSA in humans remain to be established.
• Magnitude and durability of effects under diverse metabolic states were not fully defined.

Future Directions

Validate 3-OHSA as a biomarker in clinical cohorts; delineate its receptor/targets and safety; test BAT-activating or 3-OHSA–mimetic interventions in MASLD and cardiometabolic disease.