Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
Wihuri Research Institute and Translational Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
Mol Metab. 2014 Dec 4;4(2):93-105. doi: 10.1016/j.molmet.2014.11.006. eCollection 2015 Feb.
Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown.
K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3-Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments.
We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity.
These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance.
肥胖个体的血清淋巴管生成因子 VEGF-C 和 -D 水平升高，但它们与代谢综合征的相关性尚不清楚。
K14-VEGFR-3-Ig（sR3）小鼠在皮肤中持续表达可溶性 VEGFR-3-Ig，可清除 VEGF-C 和 -D，以及野生型（WT）小鼠分别用普通饲料或高脂肪饲料喂养 20 周。为了评估 VEGFR-3 阻断对脂肪组织生长和胰岛素敏感性的影响，我们评估了体重增加、脂肪细胞大小和肝脂质积累。这些结果通过胰岛素耐量试验、脂肪组织巨噬细胞的 FACS 分析、体外 3T3-L1 分化试验和体内阻断抗体治疗实验进行补充。
我们在这里表明，sR3 小鼠免受肥胖诱导的胰岛素抵抗和肝脂质积累的影响。这种保护与皮下脂肪组织增生增强和脂肪组织中替代激活（M2）巨噬细胞数量增加有关。我们还表明，VEGF-C 和 -D 对小鼠巨噬细胞具有趋化作用，这种作用由 VEGFR-3 介导，VEGFR-3 在 M1 极化的巨噬细胞中上调。在 db/db 小鼠中系统性抗体阻断 VEGFR-3 可减少脂肪组织巨噬细胞浸润和肝脂质积累，并改善胰岛素敏感性。
这些结果揭示了淋巴管生成因子 VEGF-C 和 -D 在介导代谢综合征相关脂肪组织炎症中的意外作用。阻断这些淋巴管生成因子可能成为预防肥胖相关胰岛素抵抗的新治疗策略。
