A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate

• Published in: Cell metabolism Vol. 30; no. 1; pp. 174 - 189.e5
• Main Authors: Wang, Wenshan, Ishibashi, Jeff, Trefely, Sophie, Shao, Mengle, Cowan, Alexis J., Sakers, Alexander, Lim, Hee-Woong, O’Connor, Sean, Doan, Mary T., Cohen, Paul, Baur, Joseph A., King, M. Todd, Veech, Richard L., Won, Kyoung-Jae, Rabinowitz, Joshua D., Snyder, Nathaniel W., Gupta, Rana K., Seale, Patrick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-07-2019
• Subjects: 3-Hydroxybutyric Acid - pharmacology; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis - drug effects; Adipogenesis - genetics; adipose fibrosis; Adipose Tissue, Beige - drug effects; Adipose Tissue, Beige - metabolism; Animals; BDH1; beige fat; beta hydroxybutyrate; Blotting, Western; brown fat; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; fibro-adipogenic progenitor; Flow Cytometry; Humans; In Vitro Techniques; Male; Mass Spectrometry; Mice; PRDM16; Transcription Factors - genetics; Transcription Factors - metabolism; UCP1; adipose fibrosis; fibro-adipogenic progenitor; brown fat; beta hydroxybutyrate; BDH1; beige fat; PRDM16; UCP1
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.05.005

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or β3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite β-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.
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•Beiging stimuli decrease the fibrotic phenotype of adipose precursor cells•Aging reduces adipocyte PRDM16 expression and impairs beige fat remodeling•PRDM16 induces beta-hydroxybutyrate (BHB) secretion from adipocytes•Metabolism of BHB in precursor cells blocks fibrosis and enhances beige adipogenesis
Wang et al. show that mature adipocytes secrete beta-hydroxybutyrate (BHB), which acts on adipose precursor cells to suppress fibrosis responses and facilitate beige adipocyte differentiation. Raising BHB levels ameliorates adipose fibrosis and restores beige fat development in aged animals.