Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

  • Nat Commun. 2014 Mar 19:5:3485. doi: 10.1038/ncomms4485.
Kai Sun  1 ,  Jiyoung Park  2 ,  Olga T Gupta  3 ,  William L Holland  3 ,  Pernille Auerbach  4 ,  Ningyan Zhang  5 ,  Roberta Goncalves Marangoni  6 ,  Sarah M Nicoloro  7 ,  Michael P Czech  7 ,  John Varga  6 ,  Thorkil Ploug  4 ,  Zhiqiang An  5 ,  Philipp E Scherer  8
Affiliations
  • 1. 1] Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA [2].
  • 2. 1] Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA [2] Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST street, Ulsan 689-798, Korea [3].
  • 3. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
  • 4. Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
  • 5. Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.
  • 6. Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, Chicago, Illinois 60611-2909, USA.
  • 7. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 100, Worcester, Massachusetts 01605, USA.
  • 8. 1] Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA [2] Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
PMID: 24647224 DOI: 10.1038/ncomms4485
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.

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