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Nat Commun. 2014 Mar 19;5:3485. doi: 10.1038/ncomms4485.

Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction.

Author information

  • 11] Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA [2].
  • 21] 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].
  • 3Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
  • 4Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
  • 5Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.
  • 6Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, Chicago, Illinois 60611-2909, USA.
  • 7Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 100, Worcester, Massachusetts 01605, USA.
  • 81] 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.

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.

PMID:
24647224
[PubMed - indexed for MEDLINE]
PMCID:
PMC4076823
Free PMC Article
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