title: Divergent functions of endotrophin on different cell populations in adipose tissue.
abstract: Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Yueshui
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Xue
authors.initials: X
authors.lastname: Gu
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Kolonin
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas; and kai.sun@uth.tmc.edu.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology*; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000235:genetics; D024142:Collagen Type VI / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D006984:Hypertrophy; D007249:Inflammation / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics; D002787:Sterol Esterase / Q000235:genetics; D015854:Up-Regulation
chemical_list: D024142:Collagen Type VI; D010446:Peptide Fragments; C584135:endotrophin; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D002787:Sterol Esterase
keywords: adipose tissue; angiogenesis; endotrophin; fibrosis; inflammation