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Obesity But Not High Fat Diet Results in Lymphatic Dysfunction
Gabriela D. Garcia Nores, MD1, Daniel A. Cuzzone, MD2, Jason C. Gardenier, MD1, Ira L. Savetsky, MD1, Jeremy S. Torrisi, B.A.1, Geoffrey E. Hespe, B.S.1, Matthew D. Nitti, BA1, Raghu P. Kataru, PhD1, Babak J. Mehrara, MD1.
1Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2New York University Medical Center, New York, NY, USA.

BACKGROUND- Obesity is a well known cause of cardiovascular morbidity and has been associated with increased risk of lymphedema development. However, although it is clear that obesity decreases lymphatic function and increases inflammatory responses, whether or not these effects are due to weight gain or dietary changes alone remain unknown. Therefore, the goal of the current study was to analyze the effects of high fat diet induced obesity (HFD) on lymphatic function in obese prone and obese resistant mice.
METHODS- Adult male obesity prone (C57B6) and obesity resistant (Balb/c and MSTN) mice were fed a normal chow or HFD (60% of Kcal from fat) for 12 weeks at which time we analyzed lymphatic function, inflammation, and gene expression in isolated lymphatic endothelial cells (LEC). Correlative in vitro studies were also performed to analyze intracellular signaling pathways using isolated LECs exposed to free fatty acids (FFAs).
RESULTS- As expected, obesity prone mice gained substantially more weight than obesity resistant mice when fed a HFD. In addition, obesity prone mice fed a HFD developed leaky initial lymphatics, had significantly impaired ability to transport interstitial fluid, and demonstrated decreased trafficking of antigen presenting cells to lymph nodes as compared to lean controls and obesity resistant mice. Interestingly, we found that obesity prone mice had a marked inflammatory cell response in areas adjacent to capillary and collecting lymphatics; in contrast lean mice and obesity resistant mice had relatively little peri-lymphatic inflammatory cell accumulation. This effect correlated with marked changes in isolated LEC gene expression. For example, while obese prone mice LECs had a significant decrease in expression of lymphatic differentiation markers (VEGFR3, PROX1) and increase in inflammatory and apoptotic markers (ICAM, BAX), LECs isolated from obesity resistant mice fed a HFD had relatively normal gene expression patterns as compared to controls fed a normal chow diet. In vitro studies demonstrated that exposure of LECs to stearic acid, a long chain fatty acid known to be increased in obesity, increases cellular apoptosis and decreases LEC proliferation. More importantly, we found that inhibition of intracellular inhibitors of VEGFR3 signaling protected LECs from the harmful effects of stearic acid.
CONCLUSIONS- Our study demonstrates that HFD induced obesity is necessary for development of lymphatic dysfunction and that dietary changes alone have little effect on the lymphatic system. The negative consequences of obesity are associated with inflammatory changes surrounding lymphatic vessels and correlate with marked changes in isolated gene expression suggestive of lymphatic dedifferentiation and heightened inflammatory responses. These gene expression changes likely increase the potential for cellular injury in response to byproducts of obese tissue break down and dietary fatty acids. Our study is clinically relevant as it shows that interventions designed to prevent LEC dedifferentiation may be protective of lymphatic function in obese individuals and decrease overall inflammatory responses.

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