TY - JOUR
T1 - Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction
AU - Sun, Kai
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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U2 - 10.1038/ncomms4485
DO - 10.1038/ncomms4485
M3 - Article
C2 - 24647224
AN - SCOPUS:84921984549
SN - 2041-1723
VL - 5
SP - 3485
JO - Nature Communications
JF - Nature Communications
M1 - 3485
ER -