Dietary restriction and aerobic exercise attenuate obesity‐induced lymphatic dysfunction

Obesity is a deleterious condition characterized by excess adipose tissue deposition and a body mass index greater than 30.0. It is a major risk factor for many diseases, including coronary heart disease and non-insulin-dependent diabetes mellitus. Obesity leads to systemic low-grade inflammation caused by cytokines and adipokines. Although obesity has effects on several bodily systems, the lymphatic system is especially important since its relationship with obesity is bidirectional. Obesity is the major contributing factor to the progression and development of lymphoedema and impaired lymphatic function is thought to regulate the pathology of obesity in organ systems via modulation of the differentiation and migration of inflammatory cells. It has been shown that obesity leads to lymphatic dysfunction which is characterized by impaired lymphatic vessel pumping and density, increased lymphatic vessel leakiness, and altered lymphatic endothelial cell gene expression (Savetsky et al. 2014). Despite the clinical importance of lymphatic physiology in obese patients, an effective therapeutic strategy to regulate lymphatic function remains to be determined. In a recent study led by Nitti et al. (2016) in The Journal of Physiology, a mouse model of high-fat-diet-induced obesity was used to investigate the correlation between obesity-induced lymphatic dysfunction and weight gain. More importantly, the authors aimed to examine whether these deleterious effects of the lymphatic system can be rescued through diet-induced weight loss. Male C57BL/6J mice were placed on a high-fat diet for 12 weeks to obtain an average weight of >40 g for the experimental group. A subgroup of these obese mice were then randomly chosen to undergo diet-induced weight loss (switched to normal chow diet) for an additional 8 weeks. A group of lean mice (fed on normal chow diet throughout the course of the study) was also included as controls for all experiments. Direct dye-based imaging and immunofluorescence of lymphatic vessels were used to measure changes in morphology, pumping frequency and vessel leakiness associated with obesity. Changes in cytokine expression in obesity were determined by enzyme-linked immunosorbent assay (ELISA). Using high-end imaging, lymphangiography and lymphoscintigraphy, indices were determined to provide novel insights into changes in the lymphatic vessel function, architecture and dynamics with diet-induced weight gain and weight loss. Comparing obese mice to lean mice revealed that obesity positively correlated with lymphatic dysfunction and perilymphatic inflammation. Notably, diet-induced weight loss was able to restore lymphatic dysfunction in obese mice and normalize inflammatory responses. These findings provide direct evidence that obesity-induced lymphatic dysfunction is positively correlated with weight gain, and dietary modification can effectively improve lymphatic function and reverse obesity-induced lymphatic dysfunction. Treatment for obesity has been primarily focused on weight management. Although obesity has systemic effects, one of the consequences of the disease is lymphatic dysfunction, which is associated with corollary complications such as dermatitis and lymphoedema. In support of this idea, the authors successfully demonstrated the positive correlation between increasing weight gain and impaired lymphatic function. Interestingly, the authors point out that statistical significance was only observed when the mice reached a 40% increase in weight gain from baseline, suggesting a threshold effect from weight gain. These findings are important as it provides a cautionary threshold for obesity-related risk management which helps protect the lymphatic system in obese individuals as well as patients with lymphoedema. While the current study provides novel insights into the effects of weight management on obesity-related lymphatic dysfunction, whether exercise-induced weight loss is as effective as diet-induced weight loss for decreasing the pathology of obesity remains unanswered. A recent study from the same group by Hespe et al. (2016) investigated the impact of regular aerobic exercise on lymphatic dysfunction in obesity. Regular aerobic exercise training in obese mice was associated with markedly improved lymphatic function, but independently of weight loss. As the authors point out, its benefit should instead be focused on relieving obesity-induced perilymphatic inflammation. Although both studies suggest inflammatory mediation to be the key factor to lymphatic improvements, future studies should include the interaction between regular aerobic exercise and dietary restriction to more thoroughly examine the interdependent effects of these two behavioural adaptations. While the current study successfully assessed the role of weight loss as being one of the key determinants in improving obesity-related lymphatic dysfunction, certain technical limitations need to be taken into account. Nitti et al. (2016) acquired measurements of weight loss-induced changes in lymphatic pumping frequency through intradermal injection of indocyanine green (ICG). This approach enabled the direct assessment and comparison of lymphatic pumping frequency by measuring lymphatic vessel pulsations, with and without weight loss intervention. However, fluorescence imaging using ICG has recently been reported to be an overly simple, non-reliable technique to study lymphatic biology in vivo. Specifically, Gashev et al. (2010) were able to show that the use of ICG significantly influences the contractility of lymphatic vessels in a dose–response manner. While a low concentration of ICG (32 μm) reduces lymphatic contraction frequency by 30% 7 min post injection, administration of ICG at a concentration of 1.3 mm completely inhibited lymphatic vessel contraction frequency, introducing a significant artifact to the results acquired. Since the exact concentration of ICG present in lymphatic vessels cannot be determined in vivo, many of the quantitative values presented are potentially overestimated. As the authors mentioned in the Introduction, vascular endothelial growth factor C (VEGF-C) has been implicated to play a central role in lymphangiogenesis and lymphatic development. Depletion of VEGF-C has also been shown to protect against diet-induced obesity. In order to provide a more thorough explanation of the mechanisms behind the phenotypes observed, further studies should provide an incorporation of the role of VEGF-C in mediating the diet-induced improvement of lymphatic dysfunction caused by obesity. The rationale behind this suggestion is that perilymphatic inflammation via accumulation of T cells and macrophages was positively correlated with lymphatic dysfunction, as shown in the current study, and VEGF-C is known to be a mediator of macrophage differentiation and accumulation (Karaman et al. 2015). The interaction between VEGF-C and inducible nitric oxide synthase (iNOS) would be an elucidative one to study to help further the knowledge behind these effects as levels of iNOS were also positively associated with obesity-induced lymphatic dysfunction. Although Nitti et al. successfully demonstrated that weight management is an effective strategy against lymphatic dysfunction in obesity, these findings need to be further substantiated with larger studies due to a relatively small and inconsistent sample size throughout the study. In addition, the optimal time to incorporate weight management as a therapeutic intervention in obese patients remains to be determined. Thus, studies investigating the therapeutic effects of weight loss on the lymphatic system in early- versus late-stage obese patients may further our understanding of the underlying cellular mechanisms and help devise appropriate precautionary measures clinically. Lastly, future studies would be of particular interest to determine if the lymphatic function improving effects of weight loss in obesity is modulated by sex, as it is well established that males and females have distinct obesity pathologies, exercise capacities and adipose tissue distribution. In conclusion, Nitti et al. and Hespe et al. (2016) have demonstrated that obesity-induced lymphatic dysfunction can be significantly improved through dietary restriction and regular aerobic exercise training. Their findings provide direct evidence that lifestyle behavioural modifications, such as dietary restriction and aerobic exercise, can significantly improve and reverse obesity-induced lymphatic dysfunction. Translationally, these findings should be taken as a possible strategy for alleviating and preventing the complications of obesity on the lymphatic system, thus improving the quality of life of individuals suffering from obesity. None declared. S-H. L. and S. H-L. are supported by a Canada Graduate Scholarships–Canadian Institutes of Health Research Master's Award.

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