Whether any branching point is responsible for the phenomenon observed here GDC-0199 Bcl-2 inhibitor remains to be investigated. The diminished regulation of mRNA levels of Srebp-1c and Pck1 in Crizotinib response to insulin suggested that hepatocytes from ad libitum fatty rats might have lost responses to other hormones. Glucagon, a pancreatic hormone antagonizing insulin action , has been shown to inhibit Srebp-1c and induce Pck1 mRNA expression in hepatocytes in the absence or presence of insulin . Therefore, glucagon was used to treat hepatocytes from ad libitum lean or fatty rats. Glucagon inhibited basal and insulin-induced Srebp-1c mRNA expression in lean, but not in fatty hepatocytes from ad libitum rats. When the Pck1 mRNA expression was analyzed, glucagon induced its expression in both lean and fatty hepatocytes to the same extent without or with insulin. These results demonstrated that in fatty hepatocytes, Pck1 mRNA expression was still responsive to glucagon stimulation. It is noteworthy that insulin attenuated glucagon-mediated induction of Pck1 mRNA expression in fatty hepatocytes to the same degree as that in lean hepatocytes . It appears that part of insulin signaling system responsible for regulation of Srebp-1c and Pck1 mRNA expression was impaired in fatty hepatocytes, whereas other parts responsible for attenuation of glucagon action probably remained unchanged. The results obtained from insulin dose-response curves of Akt phosphorylation supported this conclusion. Insulin dosedependently phosphorylated Akt on Thr308 and Ser473 to the same extent in hepatocytes from ad libitum ZL or ZF rats. These results indicated that activation of Akt by insulin remains the same in lean and fatty hepatocytes. Components of insulin signal transduction pathways other than Akt may be responsible for the impaired response of Srebp-1c mRNA expression to insulin in fatty hepatocytes. It has been shown that elevation of PKCf activity contributed to the increased hepatic Srebp-1c expression in type 2 diabetic rats . In addition, insulin-induced Srebp-1c mRNA expression in primary rat hepatocytes requires mTORC1 . Whether any of these plays a role in the impairment of insulin-mediated induction of Srebp-1c mRNA in primary hepatocytes from ad libitum fatty rats remains to be investigated. As insulin induces Srebp-1c transcription via activation of liver X receptor, a nuclear receptor activated by cholesterol derivatives , the elevation of its mRNA expression in fatty hepatocytes could be caused by the excessive synthesis of endogenous agonists of LXR activation.