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

Abstract

Cold exposure induces beige adipogenesis in white adipose tissue, enhancing thermogenesis and energy expenditure. While gut microbiota-derived metabolites influence host metabolism, their role in thermogenic adaptation remains poorly defined. Here, we identify P. copri as a key microbial mediator of cold-induced adipose remodeling. Cold exposure expands P. copri in the colon, which produces 3-phenylpropionic acid (3-PPA), a metabolite that promotes beige adipocyte formation and increases energy expenditure. Mechanistically, 3-PPA signals through free fatty acid receptor 1 in M2-like macrophages, inducing chemokine C-X-C motif chemokine 13 (CXCL13) secretion, which recruits T follicular helper cells to facilitate beige adipogenesis. Lineage-tracing analyses show that adipocyte progenitor cells generate new beige adipocytes in response to 3-PPA. 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 microbiota-immune-adipose progenitor axis regulating cold adaptation and highlight microbial metabolites as potential metabolic therapies.

Keywords: 3-PPA; CXCL13; FFAR1; M2-like macrophages; Prevotella copri; UCP1; adipocyte progenitor cells; beige adipogenesis; obesity.