Fatty acid metabolism and dietary lipid composition shape B-cell responses

B-cell activation requires extensive metabolic reprogramming, yet how B cells acquire and utilize extracellular fatty acids and adapt to changes in lipid availability remains poorly understood. Here, we show that B-cell activation and the extracellular lipid environment dynamically regulate B cells. B-cell receptor (BCR) and Toll-like receptor 4 (TLR4) stimulation induced distinct mitochondrial and lipid-handling programs, differentially regulating fatty-acid uptake, cholesterol acquisition, lipid storage and mitochondrial respiration. Disrupting long-chain fatty-acid uptake, acyl-CoA activation, or mitochondrial utilisation impaired B-cell proliferation, demonstrating that multiple steps of fatty-acid metabolism are required for B-cell expansion. However, increasing extracellular fatty-acid availability alone did not enhance proliferation, indicating that fatty-acid acquisition and metabolic utilisation are functionally distinct. B cells also acquired fatty acids directly from adipocytes, identifying the local microenvironment as a potential source of metabolic substrates. In vivo, dietary fatty-acid chain length differentially shaped the germinal-centre response. A long-chain fatty-acid-rich diet increased germinal-centre B cells and T follicular helper cells and induced mitochondrial and transcriptional changes that partially converged with those observed following obesogenic feeding. Circulating lipidomics further revealed shared remodelling of lipid species between long-chain fatty-acid-rich and obesogenic diets, including altered partitioning of stearate-containing lipids. Exogenous fatty acids also modified membrane order in activated B cells, suggesting that lipid availability can influence both metabolic and biophysical properties. Together, these findings establish fatty-acid uptake, activation, and utilization as integral components of B-cell metabolic adaptation and demonstrate that dietary fatty-acid composition can remodel the lipid environment and germinal-centre response.