Based on studies in mice, FOXO1, together with SIN3A and histone deacetylases (HDACs), directly represses transcription of the GCK gene, encoding glucokinase. Insulin interferes with FOXO1-mediated repression of GCK expression, resulting in upregulation of GCK and stimulation of lipogenesis (Langlet et al. 2017).

Cytosolic glucokinase (GCK) (as well as three isoforms of hexokinase) catalyse the irreversible reaction of alpha-D-glucose (Glc) and ATP to form alpha-D-glucose-6-phosphate (G6P) and ADP, the first step in glycolysis. In the body, GCK is found only in hepatocytes and pancreatic beta cells. GCK has a high Km for Glc therefore is active when Glc is abundant such as the fed state. The rate of glucose metabolism in liver and pancreas is a function of GCK activity.

Defects in GCK are can cause maturity-onset diabetes of the young 2 (MODY2; MIM:125851), a heritable early onset form of type II diabetes. Mutations in GCK decrease the responsiveness of the beta cell to glucose leading to elevated glucose levels in the blood. GCK was the first MODY gene to be indentified and its mutations are the largest subset causing MODY, currently more than 600 across UK, Spanish and French populations. GCK utations causing MODY2 include E279*, T228M, G261R, A378T, E339K and G229R (Froguel et al. 1992, Vionnet et al. 1992, Stoffel et al. 1992, Vits et al. 2006, Shen et al. 2011).

Based on studies in mice, FOXO1 recruits transcriptional repressor SIN3A and histone deacetylases (HDACs) of the I class to the promoter of the GCK gene, encoding glucokinase (Langlet et al. 2017).

Cytosolic glucokinase (GCK) (and three isoforms of hexokinase) catalyse the irreversible reaction of alpha-D-glucose (Glc) and ATP to form alpha-D-glucose-6-phosphate (G6P) and ADP, the first step in glycolysis. In the body, GCK is found only in hepatocytes and pancreatic beta cells. GCK and the hexokinase enzymes differ in that GCK has a higher Km than the hexokinases and is less readily inhibited by the reaction product. As a result, GCK should be inactive in the fasting state when glucose concentrations are low but in the fed state should have an activity proportional to glucose concentration. These features are thought to enable efficient glucose uptake and retention in the liver, and to function as a sensor of glucose concentration coupled to insulin release in pancreatic beta cells. Defects in GCK are can cause maturity-onset diabetes of the young 2 (MODY2; MIM:125851), a heritable early onset form of type II diabetes (Hussain 2010, Osbak et al. 2009).

Cytosolic hexokinase 1 (HK1), together with isoforms HK2 and 3 and glucokinase (GCK), catalyse the irreversible reaction of alpha-D-glucose (Glc) and ATP to form alpha-D-glucose-6-phosphate (G6P) and ADP, the first step in glycolysis. HK1 is the predominant isoform of the different HKs in tissues that utilise glucose for their physiological function such as brain, lymphocytes, erythrocytes, platelets and fibroblasts. Defects in HK1 can cause hexokinase deficiency (HK deficiency; MIM:235700), a rare, autosomal recessive disease with nonspherocytic hemolytic anemia as the predominant clinical feature (Kanno 2000).

FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016).
FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).

Glucokinase