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

  • Cell Metab. 2026 Apr 7;38(4):763-778.e7. doi: 10.1016/j.cmet.2026.01.017.
Defu Li  1 ,  Bo Xia  1 ,  Ruoci Hu  2 ,  Zhao Zhang  1 ,  Cong Xu  3 ,  Hanjian Zhou  1 ,  Xiao Li  1 ,  Yonglin Hua  1 ,  Shusong Wu  4 ,  Ke Zhang  1 ,  Yuwei Jiang  5 ,  Jiangwei Wu  6 ,  Yexian Yuan  7
Affiliations
  • 1. Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
  • 2. Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 3. Ankang Municipality Agricultural Science Research Institute, Hengkou Avenue, Hengkou Demonstration Zone, Ankang City, Shaanxi 725021, China.
  • 4. Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China.
  • 5. Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA. Electronic address: [email protected].
  • 6. Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: [email protected].
  • 7. Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: [email protected].
PMID: 41742426 DOI: 10.1016/j.cmet.2026.01.017
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.
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