Nitti Matthew D, Hespe Geoffrey E, Kataru Raghu P, García Nores Gabriela D, Savetsky Ira L, Torrisi Jeremy S, Gardenier Jason C, Dannenberg Andrew J, Mehrara Babak J
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
The Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
J Physiol. 2016 Dec 1;594(23):7073-7087. doi: 10.1113/JP273061. Epub 2016 Oct 9.
Obesity induces lymphatic leakiness, decreases initial lymphatic vessel density, impairs collecting vessel pumping and decreases transport of macromolecules. Obesity results in perilymphatic inducible nitric oxide synthase (iNOS) expression and accumulation of T cells and macrophages. Deleterious effects of obesity on the lymphatic system correlate with weight gain. Weight loss restores lymphatic function in obese animals and decreases perilymphatic iNOS and inflammatory cell accumulation.
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.
肥胖会导致淋巴管渗漏，降低初始淋巴管密度，损害集合淋巴管泵血功能，并减少大分子的运输。肥胖会导致淋巴管周围诱导型一氧化氮合酶（iNOS）表达以及T细胞和巨噬细胞的积聚。肥胖对淋巴系统的有害影响与体重增加相关。体重减轻可恢复肥胖动物的淋巴功能，并减少淋巴管周围iNOS和炎症细胞的积聚。
尽管临床和实验研究表明肥胖会导致淋巴功能障碍，但这些变化是否会随着体重减轻而永久存在或可逆仍不清楚。在本研究中，我们使用饮食诱导肥胖的小鼠模型来确定肥胖诱导淋巴功能障碍的潜在细胞机制，确定这些有害影响与体重增加之间是否存在相关性，最后研究饮食诱导的体重减轻是否能使淋巴功能障碍逆转。我们报告称，肥胖与皮肤淋巴集合淋巴管泵血速率呈负相关（r = -0.9812，P < 0.0005）以及与初始淋巴管密度呈负相关（r = -0.9449，P < 0.005）。此外，我们发现体重增加与淋巴管周围炎症细胞的积聚（r = 0.9872，P < 0.0005）以及诱导型一氧化氮合酶（iNOS）的表达（r = 0.9986，P < 0.0001）之间存在显著正相关。改为正常饲料喂养8周导致体重减轻，体重下降超过25%，皮肤淋巴集合淋巴管泵血速率、淋巴管密度、淋巴管渗漏以及淋巴大分子清除均恢复正常（所有P < 0.05）。此外，体重减轻显著降低了淋巴管周围炎症和iNOS表达。综上所述，我们的研究结果表明，肥胖与淋巴功能障碍、淋巴管周围炎症和iNOS表达呈线性相关，并且通过饮食调整减轻体重可有效逆转这些有害影响。
