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Weight Loss Can Reverse Obesity-Induced Lymphatic Dysfunction
Geoffrey E. Hespe, B.S.1, Matthew D. Nitti, B.A.1, Raghu P. Kataru, Ph.D.1, Gabriela D. García Nores, M.D.1, Ira L. Savetsky, M.D.1, Jeremy S. Torrisi, B.A.1, Jason C. Gardenier, M.D.1, Andrew J. Dannenberg, M.D.2, Babak J. Mehrara, M.D.1.
1Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2Weill Cornell Medicine, New York, NY, USA.

Background: Obesity is a known risk factor for the development of both primary lymphedema, as well as secondary lymphedema following lymph node dissection. Although the pathologic consequences of obesity-induced lymphatic dysfunction have begun to be elucidated, it remains unknown whether these changes are reversible. In this study, we further identify the cellular mechanisms of obesity-induced lymphatic dysfunction and examine whether behavioral modifications, specifically weight loss, can reverse the negative effects of obesity on lymphatic function.
Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity and sacrificed at 5gm intervals starting at 25gm to analyze the effects of weight gain on lymphatic function. Other male C57BL/6J mice were maintained on either a normal chow diet (NCD) or HFD for a total of 12 weeks at which point the HFD mice were randomized to either HFD or switched to NCD to induce weight loss. Following weight loss, all mice underwent repeat lymphatic function analysis and inflammatory analysis.
Results: Interestingly, weight gain and collecting lymphatic vessel pumping frequency demonstrated a nearly linear negative correlation (r=-0.92, p<0.01). These findings also correlated with a nearly linear positive correlation between weight gain and perilymphatic inflammation and iNOS expression (r=0.99, p<0.001, r=0.97, p<0.001, respectively). In addition, we found that obese mice had leaky initial and collecting lymphatic vessels, as well as a decreased capacity to transport macromolecules. Following an approximate 25% reduction in weight while on a NCD, the negative effects of obesity on the lymphatic system were reversed with improved collecting vessel pumping frequency and decreased lymphatic leakiness. Furthermore, weight loss significantly improved metabolic parameters, reduced perilymphatic inflammation, and decreased systemic inflammatory cytokines to levels which closely mirrored what was observed in lean mice.
Conclusions: In conclusion, our findings suggest that there appears to be a linear correlation between increasing weight and inflammation and decreasing lymphatic function. More importantly, here we show that behavioral modification through weight loss can significantly ameliorate the detrimental effects of obesity on lymphatic function. These findings have clinical significance since weight loss may be a viable new mechanism for preventing the development of lymphedema in obese patients by improving lymphatic function prior to surgery.

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