Abstract 11200: Adipocyte Progenitor-Derived Proinflammatory Cells Link Adipocyte Hyperplasia and Adipose Inflammation
Visceral adipose obesity plays a pivotal role in development and progression of cardiovascular and metabolic diseases. Recent studies have shown that obesity induces active local inflammation in adipose tissue, subsequently affecting systemic metabolism and inflammatory processes in distant tissues via release of inflammatory cytokines and free fatty acids. However, it is still unclear how inflammation is initiated by obesity. Here, we report that adipocyte hyperplasia initiates adipose inflammation by generation of novel CD34+CXCR5+ proinflammatory cells from adipocyte progenitor cells. Using a high-throughput shRNA library screening system we identified RAD51, a DNA repair molecule, as an essential regulator of cell cycle progression during adipocyte differentiation (“mitotic clonal expansion”). Indeed, CD29+CD34+Sca1+ adipocyte progenitor cells isolated from Rad51+/- mice exhibited a lower propensity to differentiate into adipocytes, and high fat diet-induced adipocyte hyperplasia was also suppressed in Rad51+/- mice. Interestingly, Rad51 haploinsufficiency ameliorated high fat diet-induced adipose inflammation despite the more pronounced inflammation in the liver. These results suggest a strong link between adipocyte hyperplasia and adipose inflammation. We found that Rad51 haploinsufficiency reduced not only adipocyte progenitor cells but also CD34+CXCR5+cells. A single adipocyte progenitor cell differentiated into adipocytes and CD34+CXCR5+ cells, indicating that CD34+CXCR5+ cells are the progeny of adipocyte progenitors. In adipose tissue, CD34+CXCR5+ cells were located within the adipo-/angiogenic cell clusters, in which adipogenesis takes place. These cells express high levels of proinflammatory cytokines such as CCL2, TNF-α, IL-6 and IL-1β. Implantation of CD34+CXCR5+ cells into adipose tissue induced rapid accumulation of inflammatory monocytes/macrophages and induction of proinflammatory gene expression. Taken together, high fat diet induces adipogenesis, in which adipocyte progenitors differentiate into CD34+CXCR5+ cells as well as adipocytes. In the obese microenvironment, CD34+CXCR5+ cells produce proinflammatory cytokines and initiate inflammatory processes in adipose tissue.
- © 2011 by American Heart Association, Inc.