Sun, Kai2; Park, Jiyoung2; Gupta, Olga T2; Holland, William L2; Auerbach, Pernille6; Zhang, Ningyan3; Goncalves Marangoni, Roberta4; Nicoloro, Sarah M5; Czech, Michael P5; Varga, John4; Ploug, Thorkil6; An, Zhiqiang3; Scherer, Philipp E2
1 Section of Systems Biology Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.3 Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.4 Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, Chicago, Illinois 60611-2909, USA.5 Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 100, Worcester, Massachusetts 01605, USA.6 Section of Systems Biology Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
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.