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Obesity Induced Perilymphatic Inflammation Impairs Lymphatic Function
Gabriela D. García Nores, MD, Daniel A. Cuzzone, MD, Geoffey E. Hespe, BS, Raghu P. Kataru, PhD, Jason C. Gardenier, MD, Ira L. Savetsky, MD, Jeremy S. Torrisi, BA, Matthew D. Nitti, BA, Jessie Z. Yu, MD, Jung-Ju Huang, MD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PURPOSE:
Diet-induced obesity is a known risk factor for lymphedema. However, although it is clear that obesity is associated to lymphatic dysfunction, it remains unclear if this is due to increased subcutaneous adipose deposition or dietary toxins. The purpose of this study was therefore to evaluate the independent effects of high-fat diet (HFD) or obesity on lymphatic function in obesity-prone and obesity-resistant mice.
METHODS:
Male C57BL/6J (obesity-prone) and MSTNln or Balb/cJ (obesity-resistant) mice were maintained on a normal chow or HFD for 10weeks followed by analysis of lymphatic function. Correlative in vitro studies were performed to analyze VEGFR-3 signaling pathways in isolated lymphatic endothelial cells (LECs).
RESULTS:
Only obese mice developed leaky initial lymphatics, decreased lymphatic antigen and colloid transport function, and increased perilymphatic inflammation (p<0.001), suggesting that subcutaneous adipose deposition is necessary for this response. These findings correlated with a marked decrease in LECs gene expression of lymphatic differentiation genes VEGFR-3 and Prox1. In contrast, LECs from obesity-resistant mice had normal expression patterns as compared to their NCD controls. In vitro exposure of LECs to free fatty acid resulted in decreased VEGFR-3 expression and a dose-response decrease in cell viability. These effects were abrogated by increasing VEGFR-3 signaling.
CONCLUSION:
Our findings suggest that obesity-mediated lymphatic injury is due to increased subcutaneous adipose deposition and low-grade perilymphatic inflammation rather than direct harmful effects of dietary toxins. This lymphatic injury correlates with decreased expression of VEGFR-3 and Prox1. Increasing VEGFR-3 signaling confers significant protection to LECs and decreases lymphatic injury.


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