LAUSR

BACKGROUND Many researchers have attempted to induce lymphangiogenesis for the treatment of lymphedema. However, most previous studies had limited clinical usefulness. A high-fat diet (HFD) increases serum β-hydroxybutyrate (β-OHB) levels, which can stimulate lymphangiogenesis. The authors hypothesized that a HFD will ameliorate lymphedema through enhanced lymphangiogenesis. METHODS The effects of β-OHB on the lymphangiogenic process in human dermal lymphatic endothelial cells (HDLECs) were analyzed. A mouse tail lymphedema model was used to evaluate the effects of a HFD on lymphedema. Experimental mice were fed a HFD (45% kcal as fat, 20% as protein and 35% as carbohydrates) for 4 weeks. Tail volume was measured using the truncated cone formula. Biopsies were taken six weeks after surgical induction of lymphedema. RESULTS In HDLECs, treatment with 20 mM β-OHB increased cell viability (p = 0.008), cell migration (p = 0.011), tube formation (p = 0.005), and VEGF-C mRNA and protein expression (p < 0.001) compared with controls. HFD feeding decreased tail volume by 14.3% and fibrosis by 15.8% (p = 0.027), and increased the lymphatic vessel density (p = 0.022) and VEGF-C protein expression (p = 0.005) compared with those of operated, standard chow diet-fed mice. CONCLUSION Our findings demonstrated that β-OHB promoted lymphatic endothelial cell function and increased VEGF-C mRNA and protein expression. When mice with tail lymphedema were fed a HFD, volume and fibrosis of the tail decreased. Therefore, our findings suggest that a HFD can be a successful novel dietary approach to treating lymphedema. CLINICAL RELEVANCE STATEMENT Lymphatic regeneration after vascularized lymph node transfer can be augmented when high-fat diet is used in conjunction with vascularized lymph node transfer.