Identification of an Adipogenic Niche for Adipose Tissue Remodeling and Restoration

The regulatory events guiding progenitor activation and differentiation in adult white adipose tissue are largely unknown. We report that induction of brown adipogenesis by beta 3-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 PDGFR alpha(+) progenitors expressing CD44, a receptor for OPN. Preadipocyte proliferation is highly targeted to sites of adipocyte clearance and occurs almost exclusively in the PDGFR alpha(+) 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 PDGFR alpha(+) 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.