CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling

• Published in: Cell Vol. 182; no. 3; pp. 563 - 577.e20
• Main Authors: Oguri, Yasuo, Shinoda, Kosaku, Kim, Hyeonwoo, Alba, Diana L., Bolus, W. Reid, Wang, Qiang, Brown, Zachary, Pradhan, Rachana N., Tajima, Kazuki, Yoneshiro, Takeshi, Ikeda, Kenji, Chen, Yong, Cheang, Rachel T., Tsujino, Kazuyuki, Kim, Caroline R., Greiner, Vanille Juliette, Datta, Ritwik, Yang, Christopher D., Atabai, Kamran, McManus, Michael T., Koliwad, Suneil K., Spiegelman, Bruce M., Kajimura, Shingo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2020
• Subjects: adipocyte progenitors; Adipocytes - metabolism; adipogenesis; Adipogenesis - genetics; Adipose Tissue, Beige - cytology; Adipose Tissue, Beige - growth & development; Adipose Tissue, Beige - metabolism; Adipose Tissue, White - metabolism; Adult; Animals; Ataxin-1 - metabolism; beige fat; brown fat; diabetes; Energy Metabolism - genetics; Female; Fibronectins - pharmacology; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Humans; Inflammation - genetics; Inflammation - metabolism; Insulin Resistance - genetics; Integrins - metabolism; Male; metabolic adaptation; metabolic disease; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; obesity; Obesity - genetics; Obesity - metabolism; Receptor, Platelet-Derived Growth Factor alpha - metabolism; RNA-Seq; Signal Transduction - drug effects; Signal Transduction - genetics; Single-Cell Analysis; Stem Cells - cytology; Stem Cells - metabolism; Tetraspanin 28 - genetics; Tetraspanin 28 - metabolism; tissue remodeling; adipocyte progenitors; adipogenesis; brown fat; beige fat; metabolism; tissue remodeling; metabolic adaptation; metabolic disease; diabetes; obesity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.06.021

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/β1 and αV/β5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis. [Display omitted] •Beige fat progenitors are marked by cell surface proteins, PDGFRα, Sca1, and CD81•Beige APC proliferation is regulated by temperature, genetic background, and aging•CD81 mediates integrin-FAK signaling in response to irisin•CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation A subset of adipocyte progenitor cells give rise to beige fat through signaling responses to irisin through the action of specific integrins and the co-receptor CD81.