The FoxO transcription factors and metabolic regulation

Abstract

Forkhead transcription factors FoxOs are conserved beyond species and regulated by insulin signaling pathway. FoxOs have diverse functions on differentiation, proliferation and cell survival. In calorie restriction (CR) or starvation, FoxOs are in nucleus, active transcriptionally, and increase hepatic glucose production, decrease insulin secretion, increase food intake and cause degradation of skeletal muscle for supplying substrates for glucose production. However, even in insulin resistance due to excessive calorie intake, FoxOs are active and causes type 2 diabetes and hyperlipidemia. The understanding of molecular mechanism how FoxOs affect glucose or lipid metabolism will shed light on the novel therapy of type 2 diabetes and the metabolic syndrome.

Partial ablation of adult Drosophilainsulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance

“…16 Akt is a key kinase responsible for retaining the transcriptional factor FoxO in the cytoplasm following activation of the insulin receptor. 22 To assess insulin signaling in the periphery in our model system, the phosphorylation status of Akt isolated from thoracic flight muscles was examined. As shown in Figure 2B, a comparable level of steady-state serine phosphorylation was detected in adult IPC KD flies under RU-486 induction as compared to genetically identical flies reared on diluent containing diet (-RU) or control flies raised under the same conditions.…”

The Central Role of Glucose in Metabolism and Nutrition of Critically Ill Patients

“…Mají různé funkce v diferenciaci a proliferaci buněk, ale především se nyní pozornost zaměřuje na jejich vliv na zvyšování jaterní glukoneogeneze, degradaci glykogenu a inzulinovou rezistenci (54,55). Pochopení jejich molekulárního mechanismu tak může přispět v léčbě diabetu i kriticky nemocných pacientů.…”

Insulin Secretion and Actions

“…This phosphorylated CREB together with its coactivator, the transcriptional coactivator of regulated CREB activity 2 (TORC2) (Koo et al, 2005) then binds to the cAMP-responsive element (CRE) in the promoters of PC, PEPCK and G6Pase genes and stimulate their transcription. Under fasting conditions, FoxO also binds to its responsive element known as the insulinresponsive element (IRE) [(T/C)(G/A)AAACAA] in the promoters of PEPCK and G6Pase genes and stimulate their expression (Barthel et al, 2005;Nakae et al, 2008). Combined actions of CREB and FoxO result in the robust stimulation of gluconeogenic pathway.…”

“…However, when the level of extracellular glucose is high and the level of insulin is high, the gluconeogenic rate is inhibited. As the result of insulin signaling, Akt phosphorylates FoxO protein at Thr24, Ser256 and Ser319 residues (Barthel et al, 2005;Nakae et al, 2008), preventing its entry to the nucleus thus inhibiting transcription of PEPCK and G6Pase genes (Zhang et al, 2006). Furthermore Akt also phosphorylates TORC2 via another kinase, SIK2, at Ser 171 residue, inhibiting its entry to the nucleus (Dentin et al, 2007;Koo et al, 2005).…”