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. Creek; Natasha L. Harvey; Christopher J.H. Porter; Natalie L. Trevaskis

doi:10.1038/s42255-021-00457-w

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 journal › Article › Research › peer-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 language	English
Pages (from-to)	1175-1188
Number of pages	14
Journal	Nature Metabolism
Volume	3
Issue number	9
DOIs	https://doi.org/10.1038/s42255-021-00457-w
Publication status	Published - 20 Sept 2021

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10.1038/s42255-021-00457-w

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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., ... Trevaskis, N. L. (2021). Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity. Nature Metabolism, 3(9), 1175-1188. https://doi.org/10.1038/s42255-021-00457-w

@article{792c46910036490c9b53fc8a3963cfb9,

title = "Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity",

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 {\textquoteleft}leak{\textquoteright} 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.",

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

note = "Funding Information: We thank the Monash Animal Research Platform; the Imaging and FACS core at the Monash Institute of Pharmaceutical Sciences, particularly S. Fung for technical support; the Melbourne Mouse Metabolic Phenotyping Platform, particularly V. Haynes for technical support; T. Karnezis, St. Vincent{\textquoteright}s Institute, Melbourne, for providing human adipocytes and T. Tsiloulis, J.C.Y. Lo, D. Senyschyn and G. Chen for technical assistance. We sincerely thank surgeons G. Beban, N. Evenett, P. Johnston and A. Bartlett for their assistance with human mesenteric adipose tissue collection. This work was supported by project grants from the National Health and Medical Research Council of Australia (NHMRC grant 1100036 and NHMRC grant 1177084) and the Health Research Council of New Zealand (HRC 16-036) and the Hugo Charitable Trust (New Zealand). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

day = "20",

doi = "10.1038/s42255-021-00457-w",

language = "English",

volume = "3",

pages = "1175--1188",

journal = "Nature Metabolism",

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Cao, E, Watt, MJ, Nowell, CJ, Quach, T, Simpson, JS, De Melo Ferreira, V, Agarwal, S, Chu, H, Srivastava, A, Anderson, D , Gracia, G, Lam, A, Segal, G, Hong, J, Hu, L, Phang, KL, Escott, ABJ, Windsor, JA, Phillips, ARJ, Creek, DJ, Harvey, NL, Porter, CJH & Trevaskis, NL 2021, 'Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity', Nature Metabolism, vol. 3, no. 9, pp. 1175-1188. https://doi.org/10.1038/s42255-021-00457-w

TY - JOUR

T1 - Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity

AU - Cao, Enyuan

AU - Watt, Matthew J.

AU - Nowell, Cameron J.

AU - Quach, Tim

AU - Simpson, Jamie S.

AU - De Melo Ferreira, Vilena

AU - Agarwal, Sonya

AU - Chu, Hannah

AU - Srivastava, Anubhav

AU - Anderson, Dovile

AU - Gracia, Gracia

AU - Lam, Alina

AU - Segal, Gabriela

AU - Hong, Jiwon

AU - Hu, Luojuan

AU - Phang, Kian Liun

AU - Escott, Alistair B.J.

AU - Windsor, John A.

AU - Phillips, Anthony R.J.

AU - Creek, Darren J.

AU - Harvey, Natasha L.

AU - Porter, Christopher J.H.

AU - Trevaskis, Natalie L.

N1 - Funding Information: We thank the Monash Animal Research Platform; the Imaging and FACS core at the Monash Institute of Pharmaceutical Sciences, particularly S. Fung for technical support; the Melbourne Mouse Metabolic Phenotyping Platform, particularly V. Haynes for technical support; T. Karnezis, St. Vincent’s Institute, Melbourne, for providing human adipocytes and T. Tsiloulis, J.C.Y. Lo, D. Senyschyn and G. Chen for technical assistance. We sincerely thank surgeons G. Beban, N. Evenett, P. Johnston and A. Bartlett for their assistance with human mesenteric adipose tissue collection. This work was supported by project grants from the National Health and Medical Research Council of Australia (NHMRC grant 1100036 and NHMRC grant 1177084) and the Health Research Council of New Zealand (HRC 16-036) and the Hugo Charitable Trust (New Zealand). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/20

Y1 - 2021/9/20

N2 - 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.

AB - 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.

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U2 - 10.1038/s42255-021-00457-w

DO - 10.1038/s42255-021-00457-w

M3 - Article

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SN - 2522-5812

VL - 3

SP - 1175

EP - 1188

JO - Nature Metabolism

JF - Nature Metabolism

IS - 9

ER -

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

Abstract

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Harnessing lipid transport pathways for enhanced drug delivery

Drug targeting to sites of lymph-adipose interaction to transform the treatment of disease

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

Cite this

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

Abstract

UN SDGs

Access to Document

Other files and links

Projects

Harnessing lipid transport pathways for enhanced drug delivery

Drug targeting to sites of lymph-adipose interaction to transform the treatment of disease

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

Cite this