Obesity‐induced lymphatic dysfunction is reversible with weight loss

Abstract

Although clinical and experimental studies have shown that obesity results in lymphatic dysfunction, it remains unknown whether these changes are permanent or reversible with weight loss. In the current study, we used a mouse model of diet-induced obesity to identify putative cellular mechanisms of obesity-induced lymphatic dysfunction, determine whether there is a correlation between these deleterious effects and increasing weight gain, and finally examine whether lymphatic dysfunction is reversible with diet-induced weight loss. We report that obesity is negatively correlated with cutaneous lymphatic collecting vessel pumping rate (r = -0.9812, P < 0.0005) and initial lymphatic vessel density (r = -0.9449, P < 0.005). In addition, we show a significant positive correlation between weight gain and accumulation of perilymphatic inflammatory cells (r = 0.9872, P < 0.0005) and expression of inducible nitric oxide synthase (iNOS; r = 0.9986, P < 0.0001). Weight loss resulting from conversion to a normal chow diet for 8 weeks resulted in more than a 25% decrease in body weight and normalized cutaneous lymphatic collecting vessel pumping rate, lymphatic vessel density, lymphatic leakiness, and lymphatic macromolecule clearance (all P < 0.05). In addition, weight loss markedly decreased perilymphatic inflammation and iNOS expression. Taken together, our findings show that obesity is linearly correlated with lymphatic dysfunction, perilymphatic inflammation and iNOS expression, and that weight loss via dietary modification effectively reverses these deleterious effects.

The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

“…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 .…”

“…Progressive weight gain is directly correlated with impaired lymphatic function; however, weight loss via dietary modification also can effectively reverse these deleterious effects. For example, weight loss resulting from conversion to a normal chow diet after diet-induced obesity, resulted in more than a 25% decrease in body weight, normalized cutaneous lymphatic collecting vessel pumping rate, lymphatic vessel density, lymphatic leakiness, lymphatic macromolecule clearance and decreased perilymphatic accumulation of inflammatory cells (T cells or macrophages) (Nitti et al, 2016). Therefore, diet-induced weight loss by caloric restriction reverses the pathological effects of obesity on the lymphatic vasculature by improving lymphatic function.…”

Obesity causes lymphatic vascular injury: time for clinical translation

“…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 . ; also Garcia Nores et al . ; Hespe et al .…”

Dietary restriction and aerobic exercise attenuate obesity‐induced lymphatic dysfunction

“…In a recent study led by Nitti et al . () 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.…”

“…Nitti et al . () 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.…”