Discussion: Regulation of Adipogenesis by Lymphatic Fluid Stasis Part I. Adipogenesis, Fibrosis, and Inflammation

L dysfunction is remarkably rare after surgery, including free tissue transfers, where all lymphatic channels from flaps are severed (Fig. 1). Lymphatic regeneration must therefore be a well-worked-out biological process that functions in a wide array of clinical conditions. When lymphedema does occur, it can be a devastating clinical problem that lowers the quality of life and places tissues at risk for infection. Microscopically, we imagine excess fluid within the extracellular space deforming both cells and the surrounding extracellular matrix. We now better understand the mechanisms involved in lymph stasis and the relationship between adipogenesis, fibrosis, inflammation, and lymphedema. With the excitement of stem cells and fat grafting, a better understanding of the molecular basis for lymphedema and adipogenesis could be of great importance to plastic surgery. The mouse-tail model reported here allows a reproducible injury with which to analyze the molecular processes leading to lymphatic accumulation and its treatment. By demonstrating the proinflammatory, profibrotic, and proadipogenic states resulting from lymph stasis, the authors also may begin to provide insights into many of the complications of obesity and clinical lymphedema. We now understand that adipose tissue is much more than a simple fat storage compartment; instead, it is an active endocrine organ. Clinically, we know that morbid obesity leads to a “metabolic syndrome” with a proinflammatory state; increased insulin resistance; and, in many patients, lymphedematous extremities. However, the physical and molecular mechanisms driving lymphedema and adipogenesis are only now being discovered. Adipogenesis has become an area of intense basic and clinical study during the past decade, leading to a new understanding of preadipocyte cell lines. Preadipocytes can be induced to form mature adipocytes through treatment with dexamethasone, insulin, and methylisobutylxanthine.1 However, the in vivo signaling and differentiation pathways are complex and poorly understood. Regional mesenchymal stem cells can be induced to proliferate and expand into adipocytes and fibroblasts under inflammatory stress. Peroxisome proliferator-activated receptor, tumor necrosis factor (TNF), transforming growth factor,2 and platelet-derived growth factor receptor3 have all been shown to induce mesenchymal stem cells into adipocytes. In fact, adipocytes and fibroblasts likely have a common progenitor stem cell that leads to fibrosis in the setting of adipogenesis.3 In addition, this chemokine milieu has been found to also lead to increased extracellular matrix production and collagen type I deposition. The authors’ finding of type I collagen deposition along with adipose expansion reinforces the current understanding of coincident fibrosis and adipogenesis in inflammation. Adipogenesis can also be related to lymphoid tissue activation. Rats injected with lipopolysaccharide to the popliteal fat pad develop hypertrophy of the fat pad in a dose-dependent fashion.4 Other studies show an increase in macrophage accumulation in overweight individual and in animal studies. A recent study examining immunohistochemical staining of CD68-expressing macrophages found a significant increase in macrophage trafficking to perigonadal lymph depots in obese mice. They found macrophages in adipose tissue to be the predominant source of TNFand inducible nitric oxide synthase in adipose and proposed that obese humans might have as much as 50 percent of their macrophages localized to adipose tissue, compared with 10 percent in lean individuals.5