Obesity Impairs Lymphatic Fluid Transport and Dendritic Cell Migration to Lymph Nodes

Abstract

IntroductionObesity is a major cause of morbidity and mortality resulting in pathologic changes in virtually every organ system. Although the cardiovascular system has been a focus of intense study, the effects of obesity on the lymphatic system remain essentially unknown. The purpose of this study was to identify the pathologic consequences of diet induced obesity (DIO) on the lymphatic system.MethodsAdult male wild-type or RAG C57B6-6J mice were fed a high fat (60%) or normal chow diet for 8–10 weeks followed by analysis of lymphatic transport capacity. In addition, we assessed migration of dendritic cells (DCs) to local lymph nodes, lymph node architecture, and lymph node cellular make up.ResultsHigh fat diet resulted in obesity in both wild-type and RAG mice and significantly impaired lymphatic fluid transport and lymph node uptake; interestingly, obese wild-type but not obese RAG mice had significantly impaired migration of DCs to the peripheral lymph nodes. Obesity also resulted in significant changes in the macro and microscopic anatomy of lymph nodes as reflected by a marked decrease in size of inguinal lymph nodes (3.4-fold), decreased number of lymph node lymphatics (1.6-fold), loss of follicular pattern of B cells, and dysregulation of CCL21 expression gradients. Finally, obesity resulted in a significant decrease in the number of lymph node T cells and increased number of B cells and macrophages.ConclusionsObesity has significant negative effects on lymphatic transport, DC cell migration, and lymph node architecture. Loss of T and B cell inflammatory reactions does not protect from impaired lymphatic fluid transport but preserves DC migration capacity. Future studies are needed to determine how the interplay between diet, obesity, and the lymphatic system modulate systemic complications of obesity.

Obesity, But Not High Fat Diet, Impairs Lymphatic Function

“…To address this question, we compared lymphatic function in obesity-prone and obesityresistant mice after prolonged exposure to HFD. Our results are consistent with previous reports demonstrating that C57BL/6J mice become morbidly obese on HFD feeds, 8,9 while BALB/cJ and MSTN ln mice do not 21,22 even though serum FFA levels were significantly increased in all HFD-fed mice. 13,35 This approach is clinically relevant as the incidence and severity of obesity in patients is also highly variable and modulated by genetic factors.…”

“…[3][4][5][6][7][8][9][10] However, it remains unclear whether the observed effects on lymphatic function were secondary to weight gain, prolonged exposure to HFD or toxic metabolic by-products of adipose tissue. To address this question, we compared lymphatic function in obesity-prone and obesityresistant mice after prolonged exposure to HFD.…”

“…For example, our group and others have shown that high-fat diet (HFD)-induced obesity markedly decreases interstitial fluid transport, immune cell trafficking and lymphatic collecting vessel pumping. [8][9][10] These negative consequences were correlated with increasing body mass, suggesting that adipose deposition has a role in this response. In contrast, others have reported that high fructose diet-induced metabolic syndrome 11 or hypercholesterolemia 12 decreases collecting vessel pumping and results in lymphatic system abnormalities independent of obesity.…”

Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema

“…Standardized sections of the lymph nodes were prepared, and ferritin uptake was assessed as a percentage of the total cross-sectional area (MetaMorph software; Molecular Devices). Lymphatic function was also assessed using lymphoscintigraphy as previously described using 99m Tc sulfur colloid injected intradermally in the distal hind limb (60). ICG lymphangiography was performed using a modification of previously published techniques (61).…”

Lymphatic System in Cardiovascular Medicine

“…This could be especially important in the case of hypercholesterolemia and obesity that were shown to directly impair lymphatic vessel function. [182][183][184][185] However, in the context of the arterial wall, RCT becomes more difficult as lymphatic vessels are normally localized in the adventitia and do not occur in the intima even in advanced atherosclerotic plaques. 186 The relevance of lymphatic vessels in cholesterol metabolism and development of atherosclerosis was further demonstrated in K14-VEGFR3-Ig/lowdensity lipoprotein receptor −/− /ApoB 100/100 and Chy/low-density lipoprotein receptor −/− /ApoB 100/100 mice.…”