title: Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction.
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.
authors.affiliation: 1] Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA [2].
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: 1] 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].
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Olga T
authors.initials: OT
authors.lastname: Gupta
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Auerbach
authors.affiliation: Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, Chicago, Illinois 60611-2909, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Goncalves Marangoni
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 100, Worcester, Massachusetts 01605, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nicoloro
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 100, Worcester, Massachusetts 01605, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.affiliation: Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, Chicago, Illinois 60611-2909, USA.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Thorkil
authors.initials: T
authors.lastname: Ploug
authors.affiliation: Brown Foundation Institute of Molecular Medicine, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.affiliation: 1] 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.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000818:Animals; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D024142:Collagen Type VI; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C584135:endotrophin; D053508:Matrix Metalloproteinase 12