Summary The regulatory events guiding progenitor activation and differentiation in adult white adipose tissue are largely unknown. We report that induction of brown adipogenesis by β3-adrenergic receptor (ADRB3) activation involves the death of white adipocytes and their removal by M2-polarized macrophages. Recruited macrophages express high levels of osteopontin (OPN), which attracts a subpopulation of PDGFRα+ progenitors expressing CD44, a receptor for OPN. Preadipocyte proliferation is highly targeted to sites of adipocyte clearance and occurs almost exclusively in the PDGFRα+ CD44+ subpopulation. Knockout of OPN prevents formation of crown-like structures by ADRB3 activation and the recruitment, proliferation, and differentiation of preadipocytes. The recruitment and differentiation of PDGFRα+ progenitors are also observed following physical injury, during matrix-induced neogenesis, and in response to high-fat feeding. Each of these conditions recruits macrophages having a unique polarization signature, which may explain the timing of progenitor activation and the fate of these cells in vivo.
Bibliographical noteFunding Information:
We thank Dr. W. Richardson for providing Pdgfra-CreER mice, and Dr. C.M. Giachelli for providing OPN antibody. We thank Drs. T. Leff, R. MacKenzie, J. Wang, and members of CIMER for discussions. We also thank E. Van Buren and J. Back for technical support with FACS analyses. This study was supported by NIH grants (RO1DK62292 and RO1DK76629) to J.G.G. The Microscopy, Imaging, and Cytometry Resources Core was supported, in part, by NIH Center grant P30CA022453 to the Karmanos Cancer Institute, Wayne State University, and the Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology