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

• DOI: 10.1016/j.cmet.2019.05.005
• Publication Date: 2019-05-30T14:30:47Z
• Authors: Wenshan Wang; Jeff Ishibashi; Sophie Trefely; Mengle Shao; Alexis J. Cowan; Alexander Sakers; Hee-Woong Lim; Sean O’Connor; Mary T. Doan; Paul Cohen; Joseph A. Baur; M. Todd King; Richard L. Veech; Kyoung-Jae Won; Joshua D. Rabinowitz; Nathaniel W. Snyder; Rana K. Gupta; Patrick Seale
• Keywords: Male; 0303 health sciences; Adipogenesis; 3-Hydroxybutyric Acid; Blotting, Western; Adipose Tissue, Beige; In Vitro Techniques; Flow Cytometry; Mass Spectrometry; DNA-Binding Proteins; Mice; 03 medical and health sciences; Adipocytes; Animals; Humans; Transcription Factors

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.