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

Yasuo Oguri; Kosaku Shinoda; Hyeonwoo Kim; Diana L Alba; W Reid Bolus; Qiang Wang; Zachary Brown; Rachana N Pradhan; Kazuki Tajima; Takeshi Yoneshiro; Kenji Ikeda; Yong Chen; Rachel T Cheang; Kazuyuki Tsujino; Caroline R Kim; Vanille Juliette Greiner; Ritwik Datta; Christopher D Yang; Kamran Atabai; Michael T McManus; Suneil K Koliwad; Bruce M Spiegelman; Shingo Kajimura

doi:10.1016/j.cell.2020.06.021

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

Cell. 2020 Aug 6;182(3):563-577.e20. doi: 10.1016/j.cell.2020.06.021. Epub 2020 Jul 1.

Authors

Yasuo Oguri¹, Kosaku Shinoda², Hyeonwoo Kim³, Diana L Alba⁴, W Reid Bolus⁴, Qiang Wang¹, Zachary Brown⁵, Rachana N Pradhan⁵, Kazuki Tajima⁵, Takeshi Yoneshiro⁵, Kenji Ikeda⁶, Yong Chen⁷, Rachel T Cheang⁴, Kazuyuki Tsujino⁸, Caroline R Kim³, Vanille Juliette Greiner⁹, Ritwik Datta¹⁰, Christopher D Yang¹⁰, Kamran Atabai¹⁰, Michael T McManus⁹, Suneil K Koliwad⁴, Bruce M Spiegelman³, Shingo Kajimura¹¹

Affiliations

¹ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Beth Israel Deaconess Medical Center, Division of Endocrinology, Diabetes & Metabolism, Harvard Medical School, Boston, MA, USA.
² UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY, USA.
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
⁶ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
⁷ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan.
⁹ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Medicine, Lung Biology Center, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
¹¹ UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Beth Israel Deaconess Medical Center, Division of Endocrinology, Diabetes & Metabolism, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].

Abstract

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.

Keywords: adipocyte progenitors; adipogenesis; beige fat; brown fat; diabetes; metabolic adaptation; metabolic disease; metabolism; obesity; tissue remodeling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism
Adipogenesis / genetics*
Adipose Tissue, Beige / cytology
Adipose Tissue, Beige / growth & development
Adipose Tissue, Beige / metabolism*
Adipose Tissue, White / metabolism
Adult
Animals
Ataxin-1 / metabolism
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
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Obesity / genetics
Obesity / metabolism
RNA-Seq
Receptor, Platelet-Derived Growth Factor alpha / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics*
Single-Cell Analysis
Stem Cells / cytology
Stem Cells / metabolism*
Tetraspanin 28 / genetics
Tetraspanin 28 / metabolism*

Substances

Ataxin-1
Atxn1 protein, mouse
Cd81 protein, mouse
FNDC5 protein, mouse
Fibronectins
Integrins
Tetraspanin 28
Receptor, Platelet-Derived Growth Factor alpha
Focal Adhesion Kinase 1
Ptk2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding