Obesity-associated mesenteric lymph leakage impairs the trafficking of lipids, lipophilic drugs and antigens from the intestine to mesenteric lymph nodes

Dietary lipids, highly lipophilic drugs, antigens and immune cells are transported from the intestine to the mesenteric lymph nodes (MLNs) via mesenteric lymphatic vessels. Recently our lab reported that the mesenteric lymphatic vessels become highly branched and leak lymph to the surrounding mesenteric adipose tissue (MAT) in mice and humans with obesity, promoting insulin resistance. This study aimed to investigate the impact of obesity-associated mesenteric lymph leakage on the trafficking of a dietary lipid (oleic acid), lipophilic drug (cyclosporin A) and antigen (ovalbumin) from the intestine to MLNs. C57BL/6J mice were fed a control fat diet (CFD), or a high fat diet (HFD) for up to 35 weeks leading to obesity and impaired glucose tolerance. ¹⁴C-oleic acid, ³H-cyclosporin or Cy5.5-ovalbumin were administered orally, and blood plasma and tissues collected to measure radioactivity or fluorescence levels. The accumulation of ¹⁴C-oleic acid, ³H-cyclosporin and Cy5.5-ovalbumin in MAT was significantly increased in HFD compared to CFD fed mice, whereas in the MLNs there was less accumulation (³H-cyclosporin and Cy5.5-ovalbumin) or no significant difference (for ¹⁴C-oleic acid). The mass ratio of these molecules in MLNs compared to MAT was thus significantly decreased. Obesity-associated mesentery lymph leakage appears to divert dietary lipids, lipophilic drugs and antigens away from their normal lymphatic trafficking pathways from the intestine to MLNs and instead results in leakage into MAT. This is likely to contribute to known detrimental changes to lipid metabolism, immunotherapy and mucosal immunity in obesity.