Obesity but not high-fat diet impairs lymphatic function

Nores, Gabriela D. García; Cuzzone, Daniel; Albano, Nicholas J.; Hespe, Geoffrey E.; Kataru, Raghu P.; Torrisi, Jeremy S.; Gardenier, Jason C.; Savetsky, Ira L.; Aschen, Seth Z.; Nitti, Matthew D.; Mehrara, Babak J.

doi:10.1038/ijo.2016.96

Cited by 88 publications

(80 citation statements)

References 61 publications

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“…Dendritic cell (DC) migration was assessed 10 weeks after surgery with or without LNT using a modification of previously reported methods [29]. Briefly, the ipsilateral hindlimbs were painted with 20 μl of 8% fluorescein isothiocyanate (FITC) isomer I (5 mg/mL; Sigma-Aldrich) in a 1:1 mixture of dibutylphalate and acetone (both from Sigma-Aldrich, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema

et al. 2016

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IntroductionSecondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses.MethodsWe used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later.ResultsLNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses.ConclusionsLNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

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Section: Methodsmentioning

confidence: 99%

Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema

et al. 2016

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“…Further support for a cross-talk between lymphatics and obesity was provided by data showing that obese mice also have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, and decreased expression of lymphatic specific markers compared with lean mice (Garcia Nores et al, 2016; Hespe et al, 2016; Nitti et al, 2016; Savetsky et al, 2015a; Torrisi et al, 2016). Savetsky et al .…”

Section: A Bi-directional Cross-talk Between the Lymphatic Vasculaturmentioning

confidence: 99%

“…(2016) propose that the inflammation induced by obesity, and not HFD, is responsible for the pathologic changes observed in the lymphatic vasculature (Garcia Nores et al, 2016). Moreover, they propose that these changes are due at least in part, to direct LECs injury by products generated by inflamed adipose tissues, including long-chain free fatty acids (Garcia-Nores et al, 2016). …”

Section: A Bi-directional Cross-talk Between the Lymphatic Vasculaturmentioning

confidence: 99%

“…Additionally, we have observed that high doses of FFAs and chyle are toxic to cultured LECs due to cellular viability (Escobedo & Oliver, unpublished results). Other in vitro results have shown that exposure of LECs to stearic acid is highly toxic, resulting in a dose dependent increase in cellular apoptosis, as reflected by increasing activity of caspase-3 and Annexin V, as well as a significant decrease in Prox1 and VEGFR-3 expression levels (Garcia Nores et al, 2016). Furthermore, previous results by Sawane and collaborators revealed that elevated fatty acids in plasma of HFD-fed mice induced leakiness in the lymphatic and vascular structures via apelin depletion, producing adipocyte hypertrophy and thereby promoting obesity (Sawane et al, 2013).…”

Section: A Bi-directional Cross-talk Between the Lymphatic Vasculaturmentioning

confidence: 99%

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The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

2017

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Obesity is a key risk factor for metabolic and cardiovascular diseases, and although we understand the mechanisms regulating weight and energy balance, the causes of some forms of obesity remain enigmatic. Despite the well-established connections between lymphatics and lipids, and that intestinal lacteals play key roles in dietary fat absorption, the function of the lymphatic vasculature in adipose metabolism has only recently been recognized. It is well established that angiogenesis is tightly associated with the outgrowth of adipose tissue, as expanding adipose tissue requires increased nutrient supply from blood vessels. Results supporting a crosstalk between lymphatics and adipose tissue, and linking lymphatic function with metabolic diseases, obesity and adipose tissue also started to accumulate in the last years. Here we review our current knowledge of the mechanisms by which defective lymphatics contribute to obesity and fat accumulation in mouse models, as well as our understanding of the lymphatics-adipose tissue relationship.

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“…Importantly, HFD did not result in any changes in the deposition of fibrotic and adipose tissue, 2 hallmarks of lymphedema, and the contractility of collecting lymphatic vessels was not further impaired as a result of the diet. Recent work has demonstrated that lymphatic vessel function is protected in obesity-resistant mice in comparison to obesity-prone mice and the functional impairment is associated with significant changes in the perilymphatic inflammation [26]. …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Obesity but not high-fat diet impairs lymphatic function

Cited by 88 publications

References 61 publications

Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema

Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema

The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

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

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