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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
Author(s) -
Scioli Maria Giovanna,
Cervelli Valerio,
Arcuri Gaetano,
Gentile Pietro,
Doldo Elena,
Bielli Alessandra,
Bonanno Elena,
Orlandi Augusto
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24667
Subject(s) - oxidative stress , mapk/erk pathway , adipose tissue , microbiology and biotechnology , apoptosis , insulin , oxidative phosphorylation , signal transduction , insulin like growth factor , stem cell , insulin receptor , biology , endocrinology , growth factor , receptor , insulin resistance , genetics , biochemistry
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. J. Cell. Physiol. 229: 2077–2087, 2014. © 2014 Wiley Periodicals, Inc.