Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

Nat Commun. 2014 Mar 19;5:3485. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Adult
  • Animals
  • Collagen Type VI / genetics
  • Collagen Type VI / metabolism*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diet, High-Fat / adverse effects
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology*
  • Female
  • Fibrosis
  • Gene Expression
  • Humans
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Insulin Resistance / genetics
  • Male
  • Matrix Metalloproteinase 12 / genetics
  • Matrix Metalloproteinase 12 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Middle Aged
  • Obesity / genetics
  • Obesity / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Collagen Type VI
  • Peptide Fragments
  • Transforming Growth Factor beta
  • endotrophin
  • Matrix Metalloproteinase 12