Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity

Enyuan Cao, Matthew J. Watt, Cameron J. Nowell, Tim Quach, Jamie S. Simpson, Vilena De Melo Ferreira, Sonya Agarwal, Hannah Chu, Anubhav Srivastava, Dovile Anderson, Gracia Gracia, Alina Lam, Gabriela Segal, Jiwon Hong, Luojuan Hu, Kian Liun Phang, Alistair B.J. Escott, John A. Windsor, Anthony R.J. Phillips, Darren J. CreekNatasha L. Harvey, Christopher J.H. Porter, Natalie L. Trevaskis

Research output: Contribution to journalArticleResearchpeer-review

74 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1175-1188
Number of pages14
JournalNature Metabolism
Volume3
Issue number9
DOIs
Publication statusPublished - 20 Sept 2021

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