Abstract
Forkhead box O class proteins (FoxOs) are expressed nearly in all tissues and are involved in different functions such as energy metabolism, redox homeostasis, differentiation, and cell cycle arrest. The plasticity of FoxOs is demonstrated by post-translational modifications that determine diverse levels of transcriptional regulations also controlled by their subcellular localization. Among the different members of the FoxO family, we will focus on FoxO1 in adipose tissue, where it is abundantly expressed and is involved in differentiation and transdifferentiation processes. The capability of FoxO1 to respond differently in dependence of adipose tissue subtype underlines the specific involvement of the transcription factor in energy metabolism and the “browning” process of adipocytes. FoxO1 can localize to nuclear, cytoplasm, and mitochondrial compartments of adipocytes responding to different availability of nutrients and source of reactive oxygen species (ROS). Specifically, fasted state produced-ROS enhance the nuclear activity of FoxO1, triggering the transcription of lipid catabolism and antioxidant response genes. The enhancement of lipid catabolism, in combination with ROS buffering, allows systemic energetic homeostasis and metabolic adaptation of white/beige adipocytes. On the contrary, a fed state induces FoxO1 to accumulate in the cytoplasm, but also in the mitochondria where it affects mitochondrial DNA gene expression. The importance of ROS-mediated signaling in FoxO1 subcellular localization and retrograde communication will be discussed, highlighting key aspects of FoxO1 multifaceted regulation in adipocytes.
Highlights
The mammalian Forkhead box O (FoxO) family includes four members expressed nearly in all tissues: FoxO1, FoxO3, FoxO4, and FoxO6 [1].They are homologs of the Caenorhabditis elegans transcription factor Dauer Formation-16 (DAF-16) [1,2]and are characterized by the evolutionarily conserved forkhead domain, which is a winged-helix DNA binding motif that recognizes the core DNA motif TTGTTTAC [3]
All these findings demonstrate that FoxO1 modulation by several signaling cascades represents the master regulatory system bridging different stimuli to the physiological response of adipose tissue
The transient increase of reactive oxygen species (ROS) during adipocyte differentiation is accompanied by the upregulation of FoxO1, the transcriptional activity of which is necessary for mounting antioxidant response via the upregulation of superoxide dismutase 2 (SOD2), catalase, and Glutathione peroxidase 1 (GPx1) to avoid detrimental oxidative stress
Summary
The mammalian Forkhead box O (FoxO) family includes four members expressed nearly in all tissues: FoxO1 (forkhead in rhabdomyosarcoma, FKHR), FoxO3 (forkhead in rhabdomyosarcoma like protein 1, FKHRL1), FoxO4 (acute leukemia fusion gene located in chromosome X, AFX), and FoxO6 [1]. A wide range of external stimuli like IGF-1, insulin, cytokines, and nutrients control FoxOs activity through post-translational modifications such as phosphorylation, acetylation, methylation, and ubiquitination. These modifications alter protein subcellular localization, stability, DNA-binding properties and transcriptional activity [14]. The insulin signaling is evolutionarily conserved, it has been expectedly shown to impinge on FoxO activity in humans This pathway allows organisms to adapt to alterations in nutrient availability while maintaining systemic glucose homeostasis; for this reason, it is the key mechanism permitting FoxO protein to respond to feeding/fasting states. All post-translational modifications give a multifarious aspect to FoxO1, able to regulate its activity and subcellular localization in response to different stress conditions
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