Obesity causes lymphatic vascular injury: time for clinical translation

The global obesity pandemic currently affects more than 600 million (13% of the world's population) with numbers expected to increase further in the coming years (Barton et al. 2012). Today, annual health costs related to obesity in the USA alone are estimated between 170 to 210 billion USD. Obesity is largely due to increasing calorie intake while maintaining energy expenditure and represents the key preventable cause of atherosclerotic vascular disease, myocardial infarction and stroke and the risk factors associated with these, including diabetes, dyslipidaemia and arterial hypertension (Barton et al. 2012). Equally important, obesity has now been recognized to adversely affect susceptibility to, progression and clinical prognosis of various tumours involving lymphogenic metastasis, including pancreatic, breast and uterine cancers (Frumovitz et al. 2014; Scholz et al. 2015; Corliss et al. 2016; Kim et al. 2016). Both atherosclerotic vascular disease and cancer progression and metastasis crucially depend on immune mechanisms and endothelial cell injury both of which have become the main targets for therapeutic interventions and drug development (Barton et al. 2012; Corliss et al. 2016).

Obesity has long been known to impair lymphatic vascular function, yet the underlying mechanisms and whether changes in the lymphatic vasculature can be improved by non‐pharmacological therapeutic intervention have been not been studied so far. The study of molecular changes induced by obesity and/or diet has been facilitated by the availability of obesity‐susceptible and obesity‐resistant models of disease (Barton et al. 2012). These models not only resemble much of the disease phenotype seen in obese humans, including development of visceral obesity, insulin resistance/prediabetes, arterial endothelial cell injury, and dyslipidaemia (Barton et al. 2012) but also exhibit impaired lymphatic vessel function (Blum et al. 2014).

Only recently, new functions of vascular endothelial growth factor (VEGF), which plays a key role in angiogenesis and lymphangiogenesis and thus in tumour metastasis and progression, have been uncovered. VEGF receptor 1 signalling is enhanced in obesity and promotes macrophage polarization and tumour infiltration, thereby accelerating pancreatic and breast cancer tumour growth and metastasis (Incio et al. 2016). In line with these findings, Detmar and coworkers reported that overexpression of VEGF‐C causes weight gain, hepatic lipid accumulation and insulin resistance (Karaman et al. 2014, 2016). These investigators also uncovered that VEGF‐C and VEGF‐D are chemotactic for macrophages and that blockade of VEGF receptor 3 alleviates macrophage infiltration, fatty liver disease and impaired insulin sensitivity (Karaman et al. 2014, 2016). These findings are consistent with data reported by Alitalo and coworkers who found that a targeted deletion of VEGF‐C protects from obesity and impaired glucose metabolism; they also observed that in the intestinal lymphatic vasculature VEGF‐C maintains lipid absorption and faecal excretion of dietary cholesterol and fatty acids (Nurmi et al. 2015). Finally, obesity‐induced perilymphatic accumulation of inflammatory cells is sensitive to immunomodulatory drugs such as tacrolimus or the iNOS inhibitor 1400W (Torrisi et al. 2016).

Experimental models of human obesity have now been used by Mehrara and associates to further explore mechanisms and potential therapeutic modalities to improve obesity‐induced lymphatic injury in four recently published studies, one of them in this issue of The Journal of Physiology (Nitti et al. 2016; also Garcia Nores et al. 2016; Hespe et al. 2016; Torrisi et al. 2016). In these remarkable and comprehensive studies, the authors found that visceral obesity increases lymphatic vessel leakiness and impairs lymphatic trafficking of immune cells (Hespe et al. 2016), and impairs collecting vessel pumping and macromolecule transport while increasing perilymphatic expression of inflammatory NO synthase (iNOS) and accumulation of T cells and macrophages (Nitti et al. 2016). The authors also found that visceral obesity causes lymphatic endothelial cell injury, down‐regulation of VEGF receptor 3 and Prox1, a transcription factor required for lymphatic differentiation as well as perilymphatic lipid accumulation (Garcia Nores et al. 2016). Notably, perilymphatic inflammation was absent in an obesity‐resistant mouse strain fed the same high‐fat diet (Garcia Nores et al. 2016). Happloinsufficiency of Prox1 results in lymphatic dysfunction and adult‐onset obesity that is independent of diet (Harvey et al. 2005); recently the same investigators identified leaky lymphatic vessels as the cause of the obesity, and reported that restoration of lymphatic vascular function rescued the obesity phenotype in Prox1–/– mice (Escobado et al. 2016), consistent with the notion that the lymphatic vasculature represents a new therapeutic target for diseases associated with or aggravated by obesity.

It is clear that the findings presented in these four studies by Mehrara and coworkers have important clinical implications for the pathogenesis and treatment of diseases requiring lymphatic integrity and control of immunity, most of all cancers that show lymphogenic metastasis and lymph node spread. The findings already help to understand in part the worse clinical outcome of many forms of cancers in obese patients (Frumovitz et al. 2014; Scholz et al. 2015; Kim et al. 2016; Renehan et al. 2008, 2015). This notion is also supported by a recent study by Jung et al. which provides evidence that obesity worsens lymphnode metastasis, inflammation and angiogenesis in a model of malignant melanoma (Jung et al. 2015).

To determine whether the adverse changes are amendable, Mehrara and associates employed two of the clinically most important interventions to treat obesity (and the diabetes and hypertension associated with), weight loss and aerobic physical exercise, which are both part of the ‘endothelial therapy’ concept for atherosclerosis prevention (Barton et al. 2012). Remarkably, not only did weight loss restore lymphatic vessel function but it also normalized perivascular lymphatic inflammation (Nitti et al. 2016). Similar results have been obtained by pharmacological inhibiton of inflammatory NO synthase or T‐cell‐mediated immune responses (Torrisi et al. 2016) or by inhibiting VEGF receptor 3 function (Karaman et al. 2014, 2016). What comes as a surprise is that aerobic exercise was equally effective in inducing similar beneficial changes including normalization of endothelial expression of VEGF receptor 3, but that these beneficial effects were independent of weight loss (Hespe et al. 2016).

These new and unexpected findings call for translation into clinical applications, and suggest that ‘endothelial therapy’ that we have introduced for the arterial vasculature (Barton et al. 2012; Barton 2013) can also be applied to lymphatic vasculature. The findings reported by Mehrara et al. should stimulate the implementation of weight loss and or aerobic exercise as an adjunct therapy in patients diagnosed with or at risk of cancer. This is particularly so in view of attempts to reduce obesity and its associated diseases by drug treatments which have been largely unsuccessful or even associated with an increased risk (Barton et al. 2012; Barton 2013). It is likely that improving lymphatic endothelial and immune cell function by weight loss or by increasing cardiorespiratory fitness will translate into a better outcome in patients with diseases that depend on intact immunity and lymphatic vascular function.

Additional information

Competing interests

There are no competing interests to disclose.

Author contributions

Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

This work was supported by the Swiss National Science Foundation grants No. 108 258 and 122 504 (to M.B.), the Swiss Heart Foundation and Matching Funds of the University of Zürich (to M.H.).