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Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Author

Listed:
  • Kai Sun

    (Touchstone Diabetes Center, University of Texas Southwestern Medical Center)

  • Jiyoung Park

    (Touchstone Diabetes Center, University of Texas Southwestern Medical Center
    School of Life Sciences, Ulsan National Institute of Science and Technology)

  • Olga T. Gupta

    (Touchstone Diabetes Center, University of Texas Southwestern Medical Center)

  • William L. Holland

    (Touchstone Diabetes Center, University of Texas Southwestern Medical Center)

  • Pernille Auerbach

    (University of Copenhagen)

  • Ningyan Zhang

    (Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston)

  • Roberta Goncalves Marangoni

    (Northwestern University, Feinberg School of Medicine)

  • Sarah M. Nicoloro

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Michael P. Czech

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • John Varga

    (Northwestern University, Feinberg School of Medicine)

  • Thorkil Ploug

    (University of Copenhagen)

  • Zhiqiang An

    (Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston)

  • Philipp E. Scherer

    (Touchstone Diabetes Center, University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • 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 & Zhiq, 2014. "Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4485
    DOI: 10.1038/ncomms4485
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    Cited by:

    1. Hongyu Shen & Xun Huang & Yiheng Zhao & Dongmei Wu & Kaili Xue & Jingfei Yao & Yushuang Wang & Nan Tang & Yifu Qiu, 2022. "The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Giorgio Caratti & Ulrich Stifel & Bozhena Caratti & Ali J. M. Jamil & Kyoung-Jin Chung & Michael Kiehntopf & Markus H. Gräler & Matthias Blüher & Alexander Rauch & Jan P. Tuckermann, 2023. "Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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