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Aerobic Exercise Improves Obesity-Related Lymphatic Dysfunction Independent of Weight Loss
Geoffrey E. Hespe, BS, Jeremy S. Torrisi, BA, Ira L. Savetsky, MD, Matthew D. Nitti, BA, Gabriela D. Garcia Nores, MD, Jason C. Gardenier, MD, Raghu P. Kataru, PhD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Lymphedema is a common complication of cancer treatment and results in significant morbidity. In addition, obesity is a major risk factor for this complication with some estimates demonstrating a nearly 4 fold increase in risk. Recent prospective studies have shown that aerobic exercise can significantly decrease the symptoms of lymphedema, however, the cellular mechanisms that regulate these responses remain unknown. This is important since a better understanding of these physiologic responses may enable us to design novel treatments for this debilitating disease. Therefore, the purpose of these studies was to study the effects of exercise on lymphatic function in lean and obese mice.
Male C57B6 mice were maintained on a 60% high fat diet to induce obesity and then randomized to a sedentary group or an exercise group (30 minutes of treadmill at a rate of 10 m/min with a weekly increase of 1 m/min, 5 days a week for 6 weeks). Following completion of exercise, mice underwent lymphatic function testing, lymphatic endothelial cell (LEC) isolation to examine gene expression changes, and histology.
As expected, the relatively low level of exercise in our study did not result in weight loss as compared with sedentary animals. However, consistent with clinical findings in patients with lymphedema, we found that aerobic exercise animals had a significant increase in collecting lymphatic pumping capacity as assessed by near infra-red imaging using indocyanine green (ICG). In addition, exercise animals had increased immune cell trafficking to regional lymph nodes. Interestingly, we found that exercise significantly decreased subcutaneous and perilymphatic inflammatory cell infiltration and decreased the expression of inducible nitrous oxide synthase positive (iNOS+) cells. These changes correlated with decreased capillary lymphatic leakage and partial normalization of isolated lymphatic endothelial cell gene expression of lymphatic specific markers (VEGFR-3, Prox-1).
Our findings suggest that aerobic exercise, independent of weight loss, can improve obesity-related lymphatic dysfunction and that this response is associated with decreased perilymphatic and subcutaneous inflammation. These physiological changes alter lymphatic endothelial cell gene expression, decrease leakiness by capillary lymphatics, increase collecting lymphatic pumping capacity, and increase migration of immune cells to regional lymph nodes. Taken together, our findings show that exercise has multiple beneficial effects on lymphatic function and that these changes likely play a key role in clinical findings observed in patients with lymphedema.

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