title: High insulin-induced down-regulation of Erk-1/IGF-1R/FGFR-1 signaling is required for oxidative stress-mediated apoptosis of adipose-derived stem cells.
abstract: Homeostasis of adipose tissue requires highly coordinated response between circulating factors and cell population. Human adult adipose-derived stem cells (ASCs) display multiple differentiation properties and are sensitive to insulin stimulation. Insulin resistance and high level of circulating insulin characterize patients with type 2 diabetes and obesity. At physiological concentration, insulin promoted proliferation and survival of ASCs in vitro, whereas high insulin level induced their dose-dependent proliferative arrest and apoptosis. Insulin-induced apoptotic commitment depended on the down-regulation of Erk-1, insulin growth factor-1 receptor (IGF-1R), and fibroblast growth factor receptor-1 (FGFR-1)-mediated signaling. Specific inhibition of Erk-1/2, IGF-1R, and FGFR activity promoted ASC apoptosis but did not increase insulin effects, whereas EGFR and ErbB2 inhibition potentiated insulin-induced apoptosis. FGFRs and EGFR inhibition reduced ASC adipogenic differentiation, whereas Erk-1/2 and IGF-1R inhibition was ineffective. Insulin-induced apoptosis associated to reactive oxygen species (ROS) accumulation and inhibition of NADPH oxidase 4 (Nox4) activity prevented ASC apoptosis. Moreover, specific inhibition of Erk-1/2, IGF-1R, and FGFR-1 activity promoted ROS generation and this effect was not cumulative with that of insulin alone. Our data indicate that insulin concentration is a critical regulatory switch between proliferation and survival of ASCs. High insulin level-induced apoptotic machinery involves Nox4-generated oxidative stress and the down-regulation of a complex receptor signaling, partially distinct from that influencing adipogenic differentiation of ASCs.
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Scioli
authors.forename: Valerio
authors.initials: V
authors.lastname: Cervelli
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.forename: Pietro
authors.initials: P
authors.lastname: Gentile
authors.forename: Elena
authors.initials: E
authors.lastname: Doldo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bielli
authors.forename: Elena
authors.initials: E
authors.lastname: Bonanno
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
mesh_terms: D000273:Adipose Tissue / Q000254:growth & development / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000008:administration & dosage*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D007328:Insulin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1; D048052:Mitogen-Activated Protein Kinase 3