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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 (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.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13503 | MetaboLights | 2025-12-13

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13503_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13503_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13503.txt	Txt

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