Microbial-derived 3-phenylpropionic acid orchestrates immune–progenitor cell crosstalk to promote beige adipogenesis and energy expenditure

Cold exposure induces beige adipogenesis in white adipose tissue (iWAT), enhancing thermogenesis and energy expenditure. While gut microbiota-derived metabolites are known to regulate host metabolism, their role in thermogenic adaptation remains poorly defined. Here, we identify Prevotella copri (P. copri) as a key microbial mediator of cold-induced adipose remodeling. Cold exposure expands the population of P. copri in the colonic contents, and we found that this species that produces 3-phenylpropionic acid (3-PPA) to promote beige adipocyte formation and enhances energy expenditure. Mechanistically, 3-PPA signals through free fatty acid receptor 1 (Ffar1/Gpr40) in M2-like macrophages, inducing C-X-C motif chemokine 13 (CXCL13) secretion that in turn recruits T follicular helper (Tfh) cells to facilitate beige adipogenesis. By lineage-tracing analyses, we reveal that adipocyte progenitor cells contribute to 3-PPA-driven beige fat formation. Moreover, 3-PPA supplementation counteracts high-fat diet–induced obesity in mice and promotes thermogenesis in mouse, pig, and human adipose progenitor cells. These findings define a gut microbiota–immune cell-adipose progenitor cell axis that regulates cold adaptation, highlighting microbial metabolites as potential therapeutic targets for metabolic diseases.