Lymphedema alters lipolytic, lipogenic, immune and angiogenic properties of adipose tissue

Later stages of secondary lymphedema are associated with the massive deposition of adipose tissue (AT). The factors driving lymphedema-associated AT (LAT) expansion in humans remain rather elusive. We hypothesized that LAT expansion could be based on alterations of metabolic, adipogenic, immune and/or angiogenic qualities of AT. AT samples were acquired from upper limbs of 11 women with unilateral breast cancer-related lymphedema and 11 healthy women without lymphedema. Additional control group of 11 female breast cancer survivors without lymphedema was used to assess systemic effects of lymphedema. AT was analysed for adipocyte size, lipolysis, angiogenesis, secretion of cytokines, immune and stem cell content and mRNA gene expression. Further, adipose precursors were isolated and tested for their proliferative and adipogenic capacity. The effect of undrained LAT- derived fluid on adipogenesis was also examined. Lymphedema did not have apparent systemic effect on metabolism and cytokine levels, but it was linked with higher lymphocyte numbers and altered levels of several miRNAs in blood. LAT showed higher basal lipolysis, (lymph)angiogenic capacity and secretion of inflammatory cytokines when compared to healthy AT. LAT contained more activated CD4+ T lymphocytes than healthy AT. mRNA levels of (lymph)angiogenic markers were deregulated in LAT and correlated with markers of lipolysis. In vitro, adipose cells derived from LAT did not differ in their proliferative, adipogenic, lipogenic and lipolytic potential from cells derived from healthy AT. Nevertheless, exposition of preadipocytes to LAT-derived fluid improved their adipogenic conversion when compared with the effect of serum.

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Fig: Systemic effects of lymphedema. (A) Relative content of immune cell populations in peripheral blood, expressed as percentage of CD45+ positive cells, CD45+ positive cells within lymphogate or CD45/CD4+ positive cells within lymphogate (ANOVA of LN transformed data, Bonferroni correction for post-hoc analysis, comparison to LYM group, *p < 0.05, **p < 0.01, Mann Whitney test comparison LYM vs. NOLYM, a- p < 0.05, b- p < 0.01, c- p < 0.001). (B) Concentration of ZAG in plasma (Mann–Whitney test, comparison LYM vs. NOLYM, a-p < 0.05). (C) Levels of selected miRNA in serum. Data are presented as expression levels relative to maximal expression for each miRNA (non-parametric T-test of Log2 transformed data, *p < 0.05, **p < 0.01).

This study presents results of first complex analysis of LAT from upper limb of breast cancer survivors. Identified LAT alterations indicate a possible link between (lymph)angiogenesis and lipolysis. In addition, our in vitro results imply that AT expansion in lymphedema could be driven partially by exposition of adipose precursors to undrained LAT-derived fluid.

Koc, M., Wald, M., Varaliová, Z. et al. Lymphedema alters lipolytic, lipogenic, immune and angiogenic properties of adipose tissue: a hypothesis-generating study in breast cancer survivors. Sci Rep 11,8171 (2021). https://doi.org/10.1038/s41598-021-87494-3

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