Adipogenesis in Obesity Requires Close Interplay Between Differentiating Adipocytes, Stromal Cells, and Blood Vessels

Abstract

OBJECTIVE-The expansion of adipose tissue mass seen in obesity involves both hyperplasia and hypertrophy of adipocytes. However, little is known about how adipocytes, adipocyte precursors, blood vessels, and stromal cells interact with one another to achieve adipogenesis. RESEARCH DESIGN AND METHODS-We have developed a confocal microscopy-based method of three-dimensional visualization of intact living adipose tissue that enabled us to simultaneously evaluate angiogenesis and adipogenesis in db/db mice.RESULTS-We found that adipocyte differentiation takes place within cell clusters (which we designated adipogenic/angiogenic cell clusters) that contain multiple cell types, including endothelial cells and stromal cells that express CD34 and CD68 and bind lectin. There were close spatial and temporal interrelationships between blood vessel formation and adipogenesis, and the sprouting of new blood vessels from preexisting vasculature was coupled to adipocyte differentiation. CD34 ϩ CD68 ϩ lectin-binding cells could clearly be distinguished from CD34 Ϫ CD68 ϩ macrophages, which were scattered in the stroma and did not bind lectin. Adipogenic/angiogenic cell clusters can morphologically and immunohistochemically be distinguished from crownlike structures frequently seen in the late stages of adipose tissue obesity. Administration of anti-vascular endothelial growth factor (VEGF) antibodies inhibited not only angiogenesis but also the formation of adipogenic/angiogenic cell clusters, indicating that the coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity and that VEGF is a key mediator of that process. CONCLUSIONS-Living tissue imaging techniques providenovel evidence of the dynamic interactions between differentiating adipocytes, stromal cells, and angiogenesis in living obese adipose tissue. Diabetes

Angiogenesis and development of adipose tissue

“…These agents are also able to cause weight reduction in aged, relatively weight-stable ob/ob mice, suggesting that adipose tissue blood vessels are relatively immature and susceptible to inhibitors even when no longer growing. Another study, using life adipose tissue imaging techniques, demonstrated that angiogenesis in obesity requires a close interplay between differentiating adipocytes, stromal cells and blood cells (Nishimura et al, 2007). The use of an anti-VEGF antibody indeed inhibited not only angiogenesis, but also the formation of adipo/angiogenic cell clusters, indicating that coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity, and confirming that VEGF is a key mediator (Nishimura et al, 2007).…”

“…Another study, using life adipose tissue imaging techniques, demonstrated that angiogenesis in obesity requires a close interplay between differentiating adipocytes, stromal cells and blood cells (Nishimura et al, 2007). The use of an anti-VEGF antibody indeed inhibited not only angiogenesis, but also the formation of adipo/angiogenic cell clusters, indicating that coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity, and confirming that VEGF is a key mediator (Nishimura et al, 2007). The implication of VEGF in adipose tissue angiogenesis was also evidenced for human tissue, using anti-VEGF antibodies (Ledoux et al, 2008).…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…This is also the case with adipose tissue inflammation. Recent studies have demonstrated that obese adipose tissue exhibits adipocyte hypertrophy, immune cell infiltration, angiogenesis, and extracellular matrix overproduction during the progression of chronic inflammation [4,5,15,16]. In other words, stromal cells change dramatically in number and cell type during the course of obesity.…”

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

“…Although the present study did not address the mechanism or assess lipid profiles, perhaps an increase in angiogenesis on fat tissue was involved, in addition to adipogenesis. 51,52 Because adipose tissue is known to produce cytokines and adipokines, it remains possible that such factors may even contribute to renal disease progression.…”