In the absence of both Akt and FOXO1, the mice were able to maintain glucose homeostasis through fasting and feeding. This demonstrates that FOXO1 is intrinsically glucogenic and in its

absence, glucose homeostasis can be maintained without Akt activation. The primary function of insulin-induced Akt activation is to counteract FOXO1 and Autophagy activator thus reduce glucose production during the fed state. This study also demonstrated that FOXO1 does not inhibit the insulin mediated upregulation of anabolic processes such as glycogen and lipid synthesis.[16] The activity of FOXO1 as a regulator of blood glucose is also modulated by processes other than Akt phosphorylation. The balance between acetylation and deacetylation is a second order of regulation.

Deacetylation by NAD-dependent deacetylase sirtuin-1 (Sirt1) under conditions of cellular stress, such as that induced by oxygen free radicals, activates transcription, overriding the nuclear exclusion effect of Akt and causing nuclear translocation/retention and expression of FOXO1 target genes including those involved in gluconeogenesis.[17] Other deacetylases contribute https://www.selleckchem.com/products/AG-014699.html to FOXO1 activation as well. Class IIa histone deacetylases (HDACs) have been shown to be positive regulators of hepatic FOXO1 in response to glucagon signaling during fasting. They are phosphorylated by adenosine monophosphate activated protein kinase (AMPK) and translocated to the nucleus where they deacetylate and activate FOXOs, inducing transcription of gluconeogenic

genes.[18] Several other more novel mechanisms have also been observed to play a role in FOXO1 regulation and hepatic glucose metabolism. XBP-1, a transcription factor involved in the unfolded protein response that induces expression of genes involved in endoplasmic reticulum (ER) membrane folding, has been shown to increase insulin sensitivity. This activity is independent of its transcriptional effects but can be accounted for by its direct JAK inhibitor binding to FOXO1, acting as a chaperone to direct it to proteosomal degradation.[19] Another mechanism that appears to play a specific role in regulation of the glucuneogensis function of FOXO1 is O-GlcNAc modification.[20, 21] This glylcosylation event activates transcriptional activity of FOXOs independently of nuclear translocation and results in upregulation of glucose 6-phosphatase (G6Pase) and other gluconeogenic genes. Paradoxically, it is induced by hyperglycemia and appears to result from peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) binding to O-GlcNAc transferase and targeting it to nuclear FOXO1.[22] The second area of liver metabolic function regulated by FOXO is lipid metabolism. FOXO1 has an important role in the insulin-dependent regulation of hepatic very low density lipoprotein (VLDL) production and persistence of VLDL in the circulation.