title: HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2.
abstract: Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors, however, the underlying molecular mechanisms remain unclear. Here, we used an unbiased transcriptomics approach to identify the earliest molecular underpinnings occuring in adipose precursors following a brief HFD in mice. Our analysis identifies Heme Oxygenase-1 (HO-1) as strongly and selectively being upregulated in the adipose precursor fraction of WAT, upon high-fat diet (HFD) feeding. Specific deletion of HO-1 in adipose precursors of Hmox1fl/flPdgfraCremice enhanced HFD-dependent visceral adipose precursor proliferation and differentiation. Mechanistically, HO-1 reduces HFD-induced AKT2 phosphorylation via ROS thresholding in mitochondria to reduce visceral adipose precursor proliferation. HO-1 influences adipogenesis in a cell-autonomous way by regulating events early in adipogenesis, during the process of mitotic clonal expansion, upstream of Cebpα and PPARγ. Similar effects on human preadipocyte proliferation and differentiation in vitro were observed upon modulation of HO-1 expression. This collectively renders HO-1 as an essential factor linking extrinsic factors (HFD) with inhibition of specific downstream molecular mediators (ROS &AKT2), resulting in diminished adipogenesis that may contribute to hyperplastic adipose tissue expansion.
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Wagner
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Josefine
authors.initials: J
authors.lastname: Lindroos-Christensen
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Elisa
authors.initials: E
authors.lastname: Einwallner
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Husa
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Thea-Christin
authors.initials: TC
authors.lastname: Zapf
authors.affiliation: Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lipp
authors.affiliation: Core Facilities, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rauscher
authors.affiliation: Core Facilities, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Gröger
authors.affiliation: Core Facilities, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.affiliation: Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
authors.affiliation: Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.|Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.affiliation: University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: J Catharina
authors.initials: JC
authors.lastname: Duvigneau
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Hedwig
authors.initials: H
authors.lastname: Sutterlüty-Fall
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Klinglmüller
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Prager
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Berthold
authors.initials: B
authors.lastname: Huppertz
authors.affiliation: College of Medicine, Dong-A University, 49201 Busan, Republic of South Korea.
authors.forename: Jeanho
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.|Core Facilities, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D059305:Diet, High-Fat; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt