Plastic Surgery Research Council
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Presenter: Evan S Weitman, MD
Co-Authors: Zampell JC; Elhadad S; Aschen S; Farias-Eisner G; Cuzzone DA; Ghanta S; Albano N; Mehrara BJ
Memorial Sloan Kettering Cancer Center

Introduction: Obesity is the most significant risk factor for the development of post-surgical lymphedema, yet the cellular mechanisms underlying this phenomenon remain unclear. Therefore, the purpose of this study was to determine how diet-induced obesity (DIO) regulates lymphatic transport and physiologic function.

Methods: To test the hypothesis that diet-induced obesity regulates lymphatic function, we analyzed lymphatic transport of a radioactive colloid (lymphoscintigraphy) and trafficking of dendritic cells (DCs) in mice either fed a low fat diet or a high fat diet for 10 weeks. Furthermore, using fluorescence-activated cell sorting (FACS) we analyzed gene expression of leukocyte adhesion molecules by lymphatic endothelial cells (LECs). To confirm our in vivo findings, we analyzed interactions between isolated LECs and fat-differentiated adipose derived stem cells (ASCs).

Results: DIO mice demonstrated markedly decreased (>5-fold) lymphatic transport as assessed by lymphoscintigraphy (p<0.01). Additionally, DIO mice demonstrated significantly attenuated physiologic lymphatic function as evidenced by decreased trafficking of DCs to draining lymph nodes (50% decrease; p<0.01). We found increased expression of ICAM and CCL21 by dermal LECs isolated by FACS; this suggests that adipose deposition may encourage local upregulation of leukocyte adhesion molecules by LECs, thereby disrupting normal physiologic gradients for cellular migration to local lymph nodes. These findings were confirmed by in vitro experiments demonstrating that co-culture of LECs with fat differentiated ASCs markedly increases expression of ICAM and CCL21 as compared with co-culture with non-differentiated ASCs.

Conclusions: We have shown for the first time that DIO markedly impairs lymphatic transport and physiologic function. Importantly, these findings suggest that dietary changes may increase the risk of developing post-surgical lymphedema by directly injuring the lymphatic system. Further, our findings suggest that lymphatic dysfunction may play a role in the regulation of adipose tissue inflammation observed in obesity.

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