1.CREB and co-activators complex is the driving force for hepatic glucose production.Blood glucose levels are maintained within a narrow range (4-6 mM/L, fasting), which is crucial for protecting organisms against fasting hypoglycemia and postprandial hyperglycemia.Glucagon increases hepatic gluconeogenesis by activating the cAMPPKA signaling pathway, leading to the formation of the CREB Co-activators complex that activates the gluconeogenic gene program in the liver.On the other hand, insulin suppresses hepatic gluconeogenesis by phosphorylating of coactivators CBP and CRTC2, subsequently resulting in the disassembly of the CREB Co-activators complex.However, the function of CREB coactivator-p300 has not been fully understood.2.Different role of CBP and p300 in regulating hepatic glucose production.In glucose production assays in primary hepatocytes, we found depletion of either CBP or p300 decreased cAMP-stimulated glucose production.To assess further the role of CREB co-activators in mediating hepatic glucose production (HGP), we used adenoviral shRNAs through tail vein injection to deplete these co-activators in the liver.Depletion of p300 significantly reduced blood glucose levels in both post-prandial and fasting states, while depletion of CBP (>8 h fast) and CRTC2 (>24 h fast) reduced blood glucose levels only in the prolonged fasting state.These data indicate that p300 functions differently than CBP and CRTC2 in maintaining blood glucose levels.We further examined the role of p300, a protein closely related to CBP, in regulating gluconeogenesis and found that p300 bound constitutively to CREs due to lack of a phosphorylation site found on CBP.When a phosphorylation-competent version of p300 is expressed in the p300G442S knock-in mice, HGP becomes exquisitely sensitive to insulin and metformin suppression.P300G422S and hepatic-deleted p300 mice exhibit significant hypoglycemia and lower level of hepatic glycogen contents, indicating a role for p300 in maintaining basal HGP and glycogen metabolism.