Role of Subcutaneous Adipose Tissues in the Pathophysiology of Secondary Lymphedema

Background: Secondary lymphedema (LE) occurs due to the disruption of lymphatic circulation. Lymphatic fluid accumulation in subcutaneous tissues induces adipocyte proliferation. Obesity is an important risk factor for the occurrence and deterioration of LE. Although the relationship between LE and subcutaneous adipose tissue increase has been reported clinically, their pathophysiological relationship remains unknown. Thus, we aimed to verify whether subcutaneous adipose tissue increase is involved in the pathophysiology of secondary LE. Methods and Results: The hindlimb model of secondary LE was created using male Sprague-Dawley rats (control and LE groups; n = 5 each). Skin samples were obtained on postoperative day 168. Histological examination and quantitative real-time polymerase chain reaction analysis of inflammatory adipokines, tumor necrosis factor-alpha (Tnf-α), C-C chemokine ligand 2 (Ccl2), and interleukin-6 (Il-6) were performed. Limb volume and subcutaneous adipose tissues significantly increased in the LE group compared with those in the control. Macrophages aggregated in the augmented adipose tissues, around the adipocytes, and formed crown-like structures (CLSs). The number of CLSs significantly increased in the LE group. These macrophages expressed transforming growth factor-beta 1 (TGF-β1). Inflammatory adipokine secretion was not observed. Although Il-6 expression increased in the LE group, IL-6 was expressed in subcutaneous myofibroblasts but not in subcutaneous adipocytes. Conclusion: As TGF-β1 derived from subcutaneous myofibroblasts is involved in skin fibrosis during LE, TGF-β1 derived from adipose tissues may also play a similar role. Drug treatment for subcutaneous adipose tissue reduction may improve the skin condition in secondary LE and may be a new therapeutic strategy.