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

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

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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