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Obesity But Not High Fat Diet Impairs Lymphatic Function.
Gabriela D. Garcia Nores, M.D.1, Daniel A. Cuzzone, M.D.2, Jason C. Gardenier, M.D.1, Ira L. Savetsky, M.D.1, Jeremy S. Torrisi, B.A.1, Matthew D. Nitti, B.A.1, Geoffrey E. Hespe, B.S.1, Raghu P. Kataru, Ph.D.1, Babak J. Mehrara, M.D.1.
1Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2New York University Hospital Center, New York, NY, USA.
Although it is clear that obesity is a significant risk factor for the development of lymphedema, the mechanisms that regulate this effect remain unknown. Thus it is unclear if either dietary changes alone or progressive adipose deposition independently impair lymphatic function. Using a mouse model of high fat diet induced obesity (DIO), recent studies have shown that obese mice have significantly impaired lymphatic function. The purpose of this study was therefore to determine the independent effects of prolonged exposure to high fat diets with or without concomitant obesity on lymphatic function in mice that are genetically susceptible to DIO as compared with mice that are obesity resistant.
Male C57BL/6J (WT; obesity prone) and C57BL/6 mice with the MSTN mutation (MSTN; obesity resistant) were maintained either on a normal chow or high fat diet (HFD) for 10-12 weeks. At the conclusion of the study, we assessed lymphatic function using multiple outcome measures and analyzed changes in lymphatic endothelial cell (LEC) gene expression using PCR from cells isolated from tissues using cell sorting. To correlate our in vivo findings and identify cellular mechanisms of injury, we performed in vitro experiments using purified LECs.
As expected, HFD resulted in significant obesity, adipose deposition, and metabolic changes in WT and not in MSTN mice. Obese WT mice had significant subcutaneous tissue inflammation (p<0.001) and this finding correlated with impaired lymphatic transport function (p<0.05) as compared to their lean controls. In contrast, HFD did not result in significant alterations in lymphatic function in MSTN mice. These findings correlated with PCR analysis of cell sorted LECs collected from digested tissues of animals in the various experimental groups demonstrating significantly decreased expression of lymphatic markers (Prox-1, VEGFR3) (p<0.01) and increased expression of proapoptotic gene (Bax) (p<0.01) in obese WT but not HFD fed MSTN mice. Exposure of isolated LECs to minute concentrations of stearic acid, a long chain fatty acid known to be increased in obesity, resulted in apoptosis and impaired proliferation. In contrast, other cell types including adipose derived mesenchymal stem cells were resistant to this treatment. More importantly, we found that inhibition of intracellular inhibitors of VEGFR3 signaling protected LECs from the harmful effects of stearic acid.
Our findings show for the first time that dietary changes independent of obesity do not have significant effects on lymphatic function. We found that obesity induced subcutaneous inflammation correlates with impaired lymphatic function and is associated with marked down regulation of master lymphatic markers including Prox-1 (a molecule necessary for lymphatic differentiation) and VEGFR3 (a signaling receptor necessary for LEC proliferation and function). Exposure of isolated LECs to long chain fatty acids results in cellular apoptosis and this effect is mediated by changes in VEGFR3 signaling. Taken together, our findings suggest that obesity impairs lymphatic function by direct effects on LECs as well as indirect effects mediated by inflammation.
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