title: Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice.
abstract: Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activation of inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.|b Translational Research Center , Research Institute of Science and Technology, Tokyo University of Science , Chiba , Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Mizunoe
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.|b Translational Research Center , Research Institute of Science and Technology, Tokyo University of Science , Chiba , Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sudo
authors.affiliation: b Translational Research Center , Research Institute of Science and Technology, Tokyo University of Science , Chiba , Japan.|c Department of Internal Medicine Research , Sasaki Institute, Sasaki Foundation , Tokyo , Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Okita
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Hiraoka
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mikami
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Narahara
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Negishi
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Rikako
authors.initials: R
authors.lastname: Higashibata
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Shukoh
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Natori
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Furuichi
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Hiromine
authors.initials: H
authors.lastname: Yasukawa
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: a Laboratory of Molecular Pathology & Metabolic Disease , Faculty of Pharmaceutical Sciences, Tokyo University of Science , Chiba , Japan.|b Translational Research Center , Research Institute of Science and Technology, Tokyo University of Science , Chiba , Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000473:pathology*; D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D016922:Cellular Senescence; D059305:Diet, High-Fat; D058847:Inflammasomes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000071183:Autophagy-Related Proteins; D058847:Inflammasomes; D002403:Cathepsins
keywords: adipose tissue; autophagy; cathepsin; inflammasome; lysosome; obesity; senescence