Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that ‘leak’ HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C–VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.

内脏脂肪组织 (VAT) 包裹肠系膜淋巴管和淋巴结，淋巴液从肠和肠系膜通过这些淋巴管和淋巴结运输。肠系膜淋巴管是否有助于脂肪组织炎症和代谢以及胰岛素抵抗尚不清楚。在这里，我们表明肥胖与小鼠和人类肠系膜淋巴系统的严重和进行性功能障碍有关。我们发现，食用高脂饮食 (HFD) 的小鼠和人类的淋巴液会刺激淋巴管生长，导致形成高度分支的肠系膜淋巴管，这些淋巴管会将 HFD 淋巴液“泄漏”到 VAT 中，从而促进胰岛素抵抗。肠系膜淋巴功能障碍受环氧合酶 (COX)-2 和血管内皮生长因子 (VEGF)-C–VEGF 受体 (R)3 信号传导的调节。使用甘油酯前药方法对 COX-2 进行淋巴靶向抑制可逆转肠系膜淋巴功能障碍、内脏肥胖和炎症，并恢复小鼠的血糖控制。因此，针对肥胖相关的肠系膜淋巴功能障碍代表了治疗代谢性疾病的潜在治疗选择。