Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

TY - JOUR

T1 - Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction

AU - Sun, Kai

AU - Park, Jiyoung

AU - Gupta, Olga T

AU - Holland, William L

AU - Auerbach, Pernille

AU - Zhang, Ningyan

AU - Goncalves Marangoni, Roberta

AU - Nicoloro, Sarah M

AU - Czech, Michael P

AU - Varga, John

AU - Ploug, Thorkil

AU - An, Zhiqiang

AU - Scherer, Philipp E

PY - 2014/3

Y1 - 2014/3

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.

U2 - 10.1038/ncomms4485

DO - 10.1038/ncomms4485

M3 - Journal article

C2 - 24647224

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 3485

ER -