Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Kai Sun; Jiyoung Park; Olga T. Gupta; William L. Holland; Pernille Auerbach; Ningyan Zhang; Roberta Goncalves Marangoni; Sarah M. Nicoloro; Michael P. Czech; John Varga; Thorkil Ploug; Zhiqiang An; Philipp E. Scherer

doi:10.1038/ncomms4485

Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Kai Sun, Jiyoung Park, Olga T. Gupta, William L. Holland, Pernille Auerbach, Ningyan Zhang, Roberta Goncalves Marangoni, Sarah M. Nicoloro, Michael P. Czech, John Varga, Thorkil Ploug, Zhiqiang An, Philipp E. Scherer

Research output: Contribution to journal › Article › peer-review

260 Scopus citations

Abstract

We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the 'unhealthy' adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

Original language	English (US)
Article number	3485
Pages (from-to)	3485
Number of pages	1
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4485
State	Published - 2014

Funding

We thank R. Hammer and the Transgenic Mouse Core at University of Texas South-western Medical Center for generating TRE-endotrophin and adiponectin-rtTA mouse models; J. Shelton and the Pathology Core Facility at University of Texas Southwestern for help with histology. We thank the Metabolic Core Unit at UT Southwestern for phenotyping efforts. The work in rodents was supported by National Institutes of Health Grants R01-DK55758, R01-DK099110, and P01DK088761 (to P.E.S.); K99-DK094973 and AHA Beginning Grant in Aid 12BGI-A8910006 (to W.L.H.); and a fellowship from the Department of Defense USAMRMC BC085909 (J.P.). T.P.’s and P.A.’s contributions were carried out as a part of the research program of the UNIK: Food, Fitness & Pharma for Health and Disease (http://foodfitnesspharma.ku.dk). The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation. This work was also supported by the 2014 research fund (1.130088.01) of UNIST (Ulsan National Institute of Science and Technology) (J.P.). O.G., S.M.N. and M.P.C. were supported by National Institutes of Health Grant R01-DK030898 and the International Research Alliance of the Novo Nordisk Foundation Center for Metabolic Research.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms4485

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@article{116fe99216c3423ca385c22e946b6e3a,

title = "Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction",

abstract = "We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the 'unhealthy' adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer. ",

author = "Kai Sun and Jiyoung Park and Gupta, {Olga T.} and Holland, {William L.} and Pernille Auerbach and Ningyan Zhang and {Goncalves Marangoni}, Roberta and Nicoloro, {Sarah M.} and Czech, {Michael P.} and John Varga and Thorkil Ploug and Zhiqiang An and Scherer, {Philipp E.}",

note = "Funding Information: We thank R. Hammer and the Transgenic Mouse Core at University of Texas South-western Medical Center for generating TRE-endotrophin and adiponectin-rtTA mouse models; J. Shelton and the Pathology Core Facility at University of Texas Southwestern for help with histology. We thank the Metabolic Core Unit at UT Southwestern for phenotyping efforts. The work in rodents was supported by National Institutes of Health Grants R01-DK55758, R01-DK099110, and P01DK088761 (to P.E.S.); K99-DK094973 and AHA Beginning Grant in Aid 12BGI-A8910006 (to W.L.H.); and a fellowship from the Department of Defense USAMRMC BC085909 (J.P.). T.P.{\textquoteright}s and P.A.{\textquoteright}s contributions were carried out as a part of the research program of the UNIK: Food, Fitness & Pharma for Health and Disease (http://foodfitnesspharma.ku.dk). The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation. This work was also supported by the 2014 research fund (1.130088.01) of UNIST (Ulsan National Institute of Science and Technology) (J.P.). O.G., S.M.N. and M.P.C. were supported by National Institutes of Health Grant R01-DK030898 and the International Research Alliance of the Novo Nordisk Foundation Center for Metabolic Research.",

year = "2014",

doi = "10.1038/ncomms4485",

language = "English (US)",

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pages = "3485",

journal = "Nature communications",

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T1 - Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

AU - Sun, Kai

AU - Park, Jiyoung

AU - Gupta, Olga T.

AU - Holland, William L.

AU - Auerbach, Pernille

AU - Zhang, Ningyan

AU - Goncalves Marangoni, Roberta

AU - Nicoloro, Sarah M.

AU - Czech, Michael P.

AU - Varga, John

AU - Ploug, Thorkil

AU - An, Zhiqiang

AU - Scherer, Philipp E.

N1 - Funding Information: We thank R. Hammer and the Transgenic Mouse Core at University of Texas South-western Medical Center for generating TRE-endotrophin and adiponectin-rtTA mouse models; J. Shelton and the Pathology Core Facility at University of Texas Southwestern for help with histology. We thank the Metabolic Core Unit at UT Southwestern for phenotyping efforts. The work in rodents was supported by National Institutes of Health Grants R01-DK55758, R01-DK099110, and P01DK088761 (to P.E.S.); K99-DK094973 and AHA Beginning Grant in Aid 12BGI-A8910006 (to W.L.H.); and a fellowship from the Department of Defense USAMRMC BC085909 (J.P.). T.P.’s and P.A.’s contributions were carried out as a part of the research program of the UNIK: Food, Fitness & Pharma for Health and Disease (http://foodfitnesspharma.ku.dk). The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation. This work was also supported by the 2014 research fund (1.130088.01) of UNIST (Ulsan National Institute of Science and Technology) (J.P.). O.G., S.M.N. and M.P.C. were supported by National Institutes of Health Grant R01-DK030898 and the International Research Alliance of the Novo Nordisk Foundation Center for Metabolic Research.

PY - 2014

Y1 - 2014

N2 - We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the 'unhealthy' adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

AB - We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the 'unhealthy' adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

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DO - 10.1038/ncomms4485

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SN - 2041-1723

VL - 5

SP - 3485

JO - Nature communications

JF - Nature communications

M1 - 3485

ER -

Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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