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Cells
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The FoxO Transcription Factors and Metabolic Regulation
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The FoxO Transcription Factors and Metabolic Regulation

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 79986

Special Issue Editor

Prof. Jun Nakae

E-Mail Website
Guest Editor
Department of Physiology, International University of Health and Welfare School of Medicine, Narita 286-8686, Japan
Interests: FoxO; metabolic regulation; insulin resistance; obesity; chronic inflammation; type 2 diabetes

Special Issue Information

Dear Colleagues,

Modern lifestyles facilitate the disturbance of normal cell functions and metabolic processes. In particular, an unbalance between energy intake and expenditure, in combination with environmental factors, greatly increases the vulnerability to several diseases. At a molecular level, peripheral insulin resistance in adipose tissues, muscle, liver, and pancreatic endocrine cells provokes hyperglycaemia and a consequent increment of insulin secretion by pancreatic b cells. Multiple molecular mechanisms of insulin resistance have been described. FoxO family members, including Foxo1, Foxo3, Foxo4, and Foxo6, are phosphorylated and subsequently exported to the cytoplasm; they are inhibited by insulin/IGF1 in a PI3 kinase-dependent manner and activated by nuclear localization following oxidative stress. These transcription factors are central to the integration between environmental circumstances, including growth factor signaling and oxidative stress, and several physiological actions and provide a connection between physical well-being and the type and magnitude of metabolic regulation. Recent data have shown that FoxO Transcription Factors are involved in metabolic regulation. For example, FoxOs play important physiological roles in hepatic glucose production, fate determination of pancreatic endocrine cells, hypothalamic regulation of energy intake, and chronic inflammation. However, many processes underlying insulin resistance, chronic inflammation, and diabetes are not entirely clarified. This Special Issue aims to study multiple aspects of the metabolic regulation of FoxO Transcription Factors. We welcome original manuscripts that are highly innovative, in order to add pieces to the mosaic of knowledge of the metabolic regulation of disorders related to FoxO Transcription Factors, in an attempt to get closer to the root of the disease pathogenesis, including insulin resistance, obesity, and type 2 diabetes. Special attention will also be paid to review articles.

Prof. Jun Nakae
Guest Editor

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Keywords

  • FoxO
  • Metabolic regulation
  • Insulin resistance
  • Obesity
  • Chronic inflammation
  • Type 2 diabetes

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Published Papers (10 papers)

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Research

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15 pages, 1126 KiB  
Article
Expression of Adenoviral E1A in Transformed Cells as an Additional Factor of HDACi-Dependent FoxO Regulation
by Alisa Morshneva, Olga Gnedina, Tamara Marusova and Maria Igotti
Cells 2020, 9(1), 97; https://doi.org/10.3390/cells9010097 - 30 Dec 2019
Cited by 3 | Viewed by 3551
Abstract
The adenoviral early region 1A (E1A) protein has proapoptotic and angiogenic activity, along with its chemosensitizing effect, making it the focus of increased interest in the context of cancer therapy. It was previously shown that E1A-induced chemosensitization to different drugs, including histone deacetylases [...] Read more.
The adenoviral early region 1A (E1A) protein has proapoptotic and angiogenic activity, along with its chemosensitizing effect, making it the focus of increased interest in the context of cancer therapy. It was previously shown that E1A-induced chemosensitization to different drugs, including histone deacetylases inhibitors (HDACi), appears to be mediated by Forkhead box O (FoxO) transcription factors. In this study, we explore the relationship between E1A expression and the modulation of FoxO activity with HDACi sodium butyrate (NaBut). We show here that the basal FoxO level is elevated in E1A-expressing cells. Prolonged NaBut treatment leads to the inhibition of the FoxO expression and activity in E1A-expressing cells. However, in E1A-negative cells, NaBut promotes the transactivation ability of FoxO over time. A more detailed investigation revealed that the NaBut-induced decrease of FoxO activity in E1A-expressing cells is due to the NaBut-dependent decrease in E1A expression. Therefore, NaBut-induced inhibition of FoxO in E1A-positive cells can be overcome under unregulated overexpression of E1A. Remarkably, the CBP/p300-binding domain of E1Aad5 is responsible for stabilization of the FoxO protein. Collectively, these data show that the expression of E1A increases the FoxO stability but makes the FoxO level more sensitive to HDACi treatment. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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14 pages, 26134 KiB  
Article
Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics
by Katarina Psenakova, Klara Kohoutova, Veronika Obsilova, Michael J. Ausserlechner, Vaclav Veverka and Tomas Obsil
Cells 2019, 8(9), 966; https://doi.org/10.3390/cells8090966 - 24 Aug 2019
Cited by 33 | Viewed by 6422
Abstract
FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. [...] Read more.
FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. Moreover, all FOXO proteins are considered potential drug targets for drug resistance prevention in cancer therapy. However, the development of specific FOXO inhibitors requires a detailed understanding of structural differences between individual FOXO DNA-binding domains. The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility. These differences are encoded by variations in protein sequences and account for the distinct functions of FOXO proteins. In particular, the positions of the helices H1, H2 and H3, whose interface form the hydrophobic core of the Forkhead domain, and the interactions between hydrophobic residues located on the interface between the N-terminal segment, the H2-H3 loop, and the recognition helix H3 differ among apo FOXO1, FOXO3 and FOXO4 proteins. Therefore, the availability of apo structures of DNA-binding domains of all three major FOXO proteins will support the development of FOXO-type-specific inhibitors. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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Review

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18 pages, 1409 KiB  
Review
Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis
by Mohd Farhan, Marta Silva, Xing Xingan, Yu Huang and Wenhua Zheng
Cells 2020, 9(7), 1586; https://doi.org/10.3390/cells9071586 - 30 Jun 2020
Cited by 38 | Viewed by 8043
Abstract
Forkhead box O transcription factors (FOXOs) regulate several signaling pathways and play crucial roles in health and disease. FOXOs are key regulators of the expression of genes involved in multiple cellular processes and their deregulation has been implicated in cancer. FOXOs are generally [...] Read more.
Forkhead box O transcription factors (FOXOs) regulate several signaling pathways and play crucial roles in health and disease. FOXOs are key regulators of the expression of genes involved in multiple cellular processes and their deregulation has been implicated in cancer. FOXOs are generally considered tumor suppressors and evidence also suggests that they may have a role in the regulation of cancer metabolism and angiogenesis. In order to continue growing and proliferating, tumor cells have to reprogram their metabolism and induce angiogenesis. Angiogenesis refers to the process of new blood capillary formation from pre-existing vessels, which is an essential driving force in cancer progression and metastasis through supplying tumor cells with oxygen and nutrients. This review summarizes the roles of FOXOs in the regulation of cancer metabolism and angiogenesis. A deeper knowledge of the involvement of FOXOs in these two key processes involved in cancer dissemination may help to develop novel therapeutic approaches for cancer treatment. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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14 pages, 1757 KiB  
Review
Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms
by Laura Ioannilli, Fabio Ciccarone and Maria Rosa Ciriolo
Cells 2020, 9(4), 849; https://doi.org/10.3390/cells9040849 - 31 Mar 2020
Cited by 41 | Viewed by 6935
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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20 pages, 3242 KiB  
Review
The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution
by Michel Schmitt-Ney
Cells 2020, 9(3), 787; https://doi.org/10.3390/cells9030787 - 24 Mar 2020
Cited by 39 | Viewed by 5355
Abstract
The nematode Caenorhabditis elegans possesses a unique (with various isoforms) FOXO transcription factor DAF-16, which is notorious for its role in aging and its regulation by the insulin-PI3K-AKT pathway. In humans, five genes (including a protein-coding pseudogene) encode for FOXO transcription factors that [...] Read more.
The nematode Caenorhabditis elegans possesses a unique (with various isoforms) FOXO transcription factor DAF-16, which is notorious for its role in aging and its regulation by the insulin-PI3K-AKT pathway. In humans, five genes (including a protein-coding pseudogene) encode for FOXO transcription factors that are targeted by the PI3K-AKT axis, such as in C. elegans. This common regulation and highly conserved DNA-binding domain are the pillars of this family. In this review, I will discuss the possible meaning of possessing a group of very similar proteins and how it can generate additional functionality to more complex organisms. I frame this discussion in relation to the much larger super family of Forkhead proteins to which they belong. FOXO members are very often co-expressed in the same cell type. The overlap of function and expression creates a certain redundancy that might be a safeguard against the accidental loss of FOXO function, which could otherwise lead to disease, particularly, cancer. This is one of the points that will be examined in this “family affair” report. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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19 pages, 4797 KiB  
Review
Tissue-Specific Metabolic Regulation of FOXO-Binding Protein: FOXO Does Not Act Alone
by Noriko Kodani and Jun Nakae
Cells 2020, 9(3), 702; https://doi.org/10.3390/cells9030702 - 13 Mar 2020
Cited by 38 | Viewed by 11823
Abstract
The transcription factor forkhead box (FOXO) controls important biological responses, including proliferation, apoptosis, differentiation, metabolism, and oxidative stress resistance. The transcriptional activity of FOXO is tightly regulated in a variety of cellular processes. FOXO can convert the external stimuli of insulin, growth factors, [...] Read more.
The transcription factor forkhead box (FOXO) controls important biological responses, including proliferation, apoptosis, differentiation, metabolism, and oxidative stress resistance. The transcriptional activity of FOXO is tightly regulated in a variety of cellular processes. FOXO can convert the external stimuli of insulin, growth factors, nutrients, cytokines, and oxidative stress into cell-specific biological responses by regulating the transcriptional activity of target genes. However, how a single transcription factor regulates a large set of target genes in various tissues in response to a variety of external stimuli remains to be clarified. Evidence indicates that FOXO-binding proteins synergistically function to achieve tightly controlled processes. Here, we review the elaborate mechanism of FOXO-binding proteins, focusing on adipogenesis, glucose homeostasis, and other metabolic regulations in order to deepen our understanding and to identify a novel therapeutic target for the prevention and treatment of metabolic disorders. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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12 pages, 1890 KiB  
Review
The Emerging Roles of Fox Family Transcription Factors in Chromosome Replication, Organization, and Genome Stability
by Yue Jin, Zhangqian Liang and Huiqiang Lou
Cells 2020, 9(1), 258; https://doi.org/10.3390/cells9010258 - 20 Jan 2020
Cited by 28 | Viewed by 5056
Abstract
The forkhead box (Fox) transcription factors (TFs) are widespread from yeast to humans. Their mutations and dysregulation have been linked to a broad spectrum of malignant neoplasias. They are known as critical players in DNA repair, metabolism, cell cycle control, differentiation, and aging. [...] Read more.
The forkhead box (Fox) transcription factors (TFs) are widespread from yeast to humans. Their mutations and dysregulation have been linked to a broad spectrum of malignant neoplasias. They are known as critical players in DNA repair, metabolism, cell cycle control, differentiation, and aging. Recent studies, especially those from the simple model eukaryotes, revealed unexpected contributions of Fox TFs in chromosome replication and organization. More importantly, besides functioning as a canonical TF in cell signaling cascades and gene expression, Fox TFs can directly participate in DNA replication and determine the global replication timing program in a transcription-independent mechanism. Yeast Fox TFs preferentially recruit the limiting replication factors to a subset of early origins on chromosome arms. Attributed to their dimerization capability and distinct DNA binding modes, Fkh1 and Fkh2 also promote the origin clustering and assemblage of replication elements (replication factories). They can mediate long-range intrachromosomal and interchromosomal interactions and thus regulate the four-dimensional chromosome organization. The novel aspects of Fox TFs reviewed here expand their roles in maintaining genome integrity and coordinating the multiple essential chromosome events. These will inevitably be translated to our knowledge and new treatment strategies of Fox TF-associated human diseases including cancer. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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10 pages, 1861 KiB  
Review
A Review of FoxO1-Regulated Metabolic Diseases and Related Drug Discoveries
by Shiming Peng, Wei Li, Nannan Hou and Niu Huang
Cells 2020, 9(1), 184; https://doi.org/10.3390/cells9010184 - 10 Jan 2020
Cited by 86 | Viewed by 9226
Abstract
FoxO1 is a conserved transcription factor involved in energy metabolism. It is tightly regulated by modifications on its mRNA and protein and responds to environmental nutrient signals. FoxO1 controls the transcription of downstream genes mediating metabolic regulation. Dysfunction of FoxO1 pathways results in [...] Read more.
FoxO1 is a conserved transcription factor involved in energy metabolism. It is tightly regulated by modifications on its mRNA and protein and responds to environmental nutrient signals. FoxO1 controls the transcription of downstream genes mediating metabolic regulation. Dysfunction of FoxO1 pathways results in several metabolic diseases, including diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Here, we summarize the mechanism of FoxO1 regulation behind these diseases and FoxO1-related drug discoveries. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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15 pages, 780 KiB  
Review
DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling
by Aleksandra Zečić and Bart P. Braeckman
Cells 2020, 9(1), 109; https://doi.org/10.3390/cells9010109 - 2 Jan 2020
Cited by 122 | Viewed by 16628
Abstract
DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the [...] Read more.
DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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15 pages, 748 KiB  
Review
Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction
by Yizhou Jiang, Fengxia Yan, Zhongping Feng, Philip Lazarovici and Wenhua Zheng
Cells 2020, 9(1), 100; https://doi.org/10.3390/cells9010100 - 31 Dec 2019
Cited by 32 | Viewed by 5307
Abstract
Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms [...] Read more.
Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms by which DR confers benefits on longevity were not yet fully elucidated. The forkhead box O transcription factors (FOXOs), identified as downstream regulators of the insulin/IGF-1 signaling pathway, control the expression of many genes regulating crucial biological processes such as metabolic homeostasis, redox balance, stress response and cell viability and proliferation. The activity of FOXOs is also mediated by AMP-activated protein kinase (AMPK), sirtuins and the mammalian target of rapamycin (mTOR). Therefore, the FOXO-related pathways form a complex network critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis and to support physiological aging. In this review, we will focus on the role of FOXOs in different DR interventions. As different DR regimens or calorie (energy) restriction mimetics (CRMs) can elicit both distinct and overlapped DR-related signaling pathways, the benefits of DR may be maximized by combining diverse forms of interventions. In addition, a better understanding of the precise role of FOXOs in different mechanistic aspects of DR response would provide clear cellular and molecular insights on DR-induced increase of lifespan and health-span. Full article
(This article belongs to the Special Issue The FoxO Transcription Factors and Metabolic Regulation)
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