Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema

Abstract

Although obesity is a major clinical risk factor for lymphedema, the mechanisms that regulate this effect remain unknown. Recent reports have demonstrated that obesity is associated with acquired lymphatic dysfunction. The purpose of this study was to determine how obesity-induced lymphatic dysfunction modulates the pathological effects of lymphatic injury in a mouse model. We used a diet-induced model of obesity in adult male C57BL/6J mice in which experimental animals were fed a high-fat diet and control animals were fed a normal chow diet for 8-10 wk. We then surgically ablated the superficial and deep lymphatics of the midportion of the tail. Six weeks postoperatively, we analyzed changes in lymphatic function, adipose deposition, inflammation, and fibrosis. We also compared responses to acute inflammatory stimuli in obese and lean mice. Compared with lean control mice, obese mice had baseline decreased lymphatic function. Lymphedema in obese mice further impaired lymphatic function and resulted in increased subcutaneous adipose deposition, increased CD45(+) and CD4(+) cell inflammation (P < 0.01), and increased fibrosis, but caused no change in the number of lymphatic vessels. Interestingly, obese mice had a significantly increased acute inflammatory reaction to croton oil application. In conclusion, obese mice have impaired lymphatic function at baseline that is amplified by lymphatic injury. This effect is associated with increased chronic inflammation, fibrosis, and adipose deposition. These findings suggest that obese patients are at higher risk for lymphedema due to impaired baseline lymphatic clearance and an increased propensity for inflammation in response to injury.

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

“…This hypothesis is also supported by previous studies demonstrating that CD4 + cells are key regulators of smooth muscle cell proliferation and atherosclerosis (46)(47)(48), as well as studies demonstrating that ECM composition is a key regulator of interstitial fluid transport (49). Progressive lymphatic and ECM fibrosis also provides a rationale for known risk factors of lymphedema, such as radiation and obesity, as these factors independently increase fibrosis (50)(51)(52). Indeed, previous studies have shown that radiation-induced fibrosis markedly decreases interstitial fluid transport and that inhibition of fibrosis effectively preserves lymphatic function independent of LEC survival in this setting (53).…”

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.…”

Influence of body mass index on the frequency of lymphedema and other complications after surgery for breast cancer

“…Studies suggest that potential risk factors for developing lymphedema include radiation therapy, infection, axillary dissection, type of surgery, the number of lymph nodes removed and involved, and obesity. Even though it is not known whether these factors affect the severity of lymphedema 6 , obesity can be associated with increased chronic inflammation, fibrosis and adipose deposition 9 , therefore obese or overweight women are at higher risk for lymphedema. The purpose of this study was to investigate the influence of BMI of women who underwent survey with axillary dissection for breast cancer on the occurrence of lymphedema and other complications such as scar tissue adhesion, pain, and heaviness in the upper limb within two years after surgery.…”