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https://hdl.handle.net/2440/132912
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Type: | Journal article |
Title: | Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity |
Author: | Cao, E. Watt, M.J. Nowell, C.J. Quach, T. Simpson, J.S. De Melo Ferreira, V. Agarwal, S. Chu, H. Srivastava, A. Anderson, D. Gracia, G. Lam, A. Segal, G. Hong, J. Hu, L. Phang, K.L. Escott, A.B.J. Windsor, J.A. Phillips, A.R.J. Creek, D.J. et al. |
Citation: | Nature Metabolism, 2021; 3(9):1175-1188 |
Publisher: | Springer Nature |
Issue Date: | 2021 |
ISSN: | 2522-5812 2522-5812 |
Statement of Responsibility: | 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. Creek, Natasha L. Harvey, Christopher J.H. Porter, and Natalie L. Trevaskis |
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. |
Keywords: | Mesentery Lymphatic Vessels Animals Mice, Inbred C57BL Humans Mice Rats Rats, Sprague-Dawley Insulin Resistance Vascular Endothelial Growth Factor C Signal Transduction Adult Aged Middle Aged Female Male Intra-Abdominal Fat Cyclooxygenase 2 Obesity, Abdominal |
Rights: | © The Author(s), under exclusive licence to Springer Nature Limited 2021 |
DOI: | 10.1038/s42255-021-00457-w |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1100036 http://purl.org/au-research/grants/nhmrc/1177084 |
Published version: | http://dx.doi.org/10.1038/s42255-021-00457-w |
Appears in Collections: | Medicine publications |
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