Cold-Induced Serum Short-Chain Fatty Acids Act as Markers of Brown Adipose Tissue Metabolism in Humans.

Abstract

Short-chain fatty acids (SCFAs) produced from dietary fiber fermentation can regulate adipose tissue metabolism through signaling pathways involving G protein-coupled receptors and histone deacetylase inhibition. While preclinical studies suggest they enhance thermogenesis, their role in human brown adipose tissue (BAT) under different thermal conditions remains unclear. This study explores the associations between circulating SCFAs and human BAT metabolism at room temperature and after cold exposure. This cross-sectional study included data from 71 adults (aged 20-55 years, body mass index 19-44 kg/m2). Dynamic [15O]O2, [15O]H2O, [¹⁸F]FDG, and [¹⁸F]FTHA positron emission tomography/computed tomography scans were used to assess BAT metabolism. Serum SCFAs were quantified using liquid chromatography-mass spectrometry, and gene expression in biopsy-excised BAT samples (n = 14) was analyzed. Participants were stratified into low- and high-BAT groups based on [¹⁸F]FDG or [¹⁸F]FTHA uptakes. Cold-induced acetate and propionate were positively associated with key in vivo BAT metabolism indicators, namely nonesterified fatty acid (NEFA) uptake and oxygen consumption. Only in the high-BAT group were circulating SCFAs maintained after cold exposure. BAT transcriptome revealed that genes involved in SCFA metabolism (such as conversion to acetyl-CoA) correlated with thermogenic and lipid metabolism genes exclusively in the high-BAT group, suggesting a distinct molecular link between SCFA pathways and BAT function. Circulating SCFAs are linked with BAT oxidative metabolism and NEFA uptake during cold exposure. The observed correlations between SCFA catabolic genes and thermogenic markers suggest that metabolically active BAT may selectively engage SCFA-related pathways, pointing to a potential mechanistic role of SCFAs in supporting BAT function in humans.