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Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells and blood vessels

¹Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan
²Nano-Bioengineering Education Program, PRESTO, Japan Science and Technology Agency, Tokyo, Japan
³Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
⁴Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

Correspondence: sugiura{at}k.u-tokyo.ac.jp

Key Words: obesity • angiogenesis • adipogenesis.

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 3-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 take place within cell clusters, which we designated adipo-/angiogenic cell clusters, containing 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. The CD34⁺ CD68⁺, lectin-binding cells could be clearly distinguished from CD34^- CD68⁺ macrophages, which were scattered in the stroma and did not bind lectin. Adipo-/angiogenic cell clusters can be morphologically and immunohistochemically distinguished from crown-like structures frequently seen in the late stages of adipose tissue obesity. Administration of anti-vascular endothelial growth factor (VEGF) antibody inhibited not only angiogenesis but also the formation of adipo-/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 imaing technique provide novel evidence of the dynamic interactions between differentiating adipocytes, stromal cells and angiogenesis in living obese adipose tissue.

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