High-Fat Diet in the Absence of Obesity Does Not Aggravate Surgically Induced Lymphoedema in Mice

Abstract

Background: Lymphoedema represents the cardinal manifestation of lymphatic dysfunction and is associated with expansion of the adipose tissue in the affected limb. In mice, high-fat diet (HFD)-induced obesity was associated with impaired collecting lymphatic vessel function, and adiposity aggravated surgery-induced lymphoedema in a mouse model. The aim of the current study was to investigate whether adiposity is necessary to impair lymphatic function or whether increased lipid exposure alone might be sufficient in a surgical lymphoedema model. Methods: To investigate the role of increased lipid exposure in lymphoedema development we used a well-established mouse tail lymphoedema model. Female mice were subjected to a short-term (6 weeks) HFD, without development of obesity, before surgical induction of lymphedema. Lymphoedema was followed over a period of 6 weeks measuring oedema, evaluating tissue histology and lymphatic vascular function. Results: HFD increased baseline angiogenesis and average lymphatic vessel size in comparison to the chow control group. Upon induction of lymphedema, HFD-treated mice did not exhibit aggravated oedema and no morphological differences were observed in the blood and lymphatic vasculature. Importantly, the levels of fibro-adipose tissue deposition were comparable between the 2 groups and lymphatic vessel function was not impaired as a result of the HFD. Although the net immune cell infiltration was comparable, the HFD group displayed an increased infiltration of macrophages, which exhibited an M2 polarization phenotype. Conclusions: These results indicate that increased adiposity rather than dietary influences determines predisposition to or severity of lymphedema.

Histopathologic Features of Lymphedema: A Molecular Review

“…Detmar and colleagues reported similar associations between obesity and lymphedema in mice with high-fat diet-induced obesity in which adiposity was associated with impaired collecting lymphatics [54]. This effect on of 13 lymphatic function was independent of lipid exposure as high-fat diet in the absence of obesity did not worsen lymphedema [55].…”

Mechanisms of Connexin-Related Lymphedema

“…Lymphedema in adult mice has only been demonstrated in a few cases where lymphatic tracts/valves are severely disrupted or missing altogether. Examples include 1) the mouse tail model in which both superficial and deep (collecting) lymphatic vessels are disrupted surgically, resulting in measurable swelling of the tail circumference within a few days, but which subsequently resolves as newly-formed vessels bridge the damaged region 122–124 ; 2) Chy mice, with altered VEGFR3 signaling, lack initial and collecting lymphatics in some regions (including the hindlimb) and exhibit elevated interstitial hydrostatic pressure and hindpaw swelling 125 . Human patients with lymphatic tract disruption due to surgery or VEGFR3 mutations also develop lymphedema 80–82, 126 .…”

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

“…Imaging of body composition in patients with lymphedema identified SAT deposition in the affected limbs with some intramuscular fat infiltration [ 14 , 75 , 76 , 77 , 78 ]. SAT expansion may be indicative of inflammation and fibrosis rather than metabolic imbalance, though obesity exacerbates lymphedema in experimental models [ 79 , 80 ]. Additionally, vascular function in relation to SAT deposition, in particular potential clearance by lymphatics, deserves further attention.…”

“…Lymphatic dysfunction in genetic mouse models, for instance, can drive subcutaneous adipose expansion [ 81 , 82 ]. Adipose expansion can also impede lymphatic function, creating a potentially vicious cycle in lymphedema [ 79 , 80 , 83 ]. These provocative mechanistic possibilities would be interesting to observe in human disease with further development of noninvasive lymphatic-imaging technologies [ 84 ].…”