Selective Pharmacological Inhibition of S6K1 Improves Glucose Metabolism In Vitro and In Vivo in High-Fat-Fed Obese Mice

Abstract

The mammalian target of rapamycin (RAP) complex 1 (mTORC1) and its downstream effector S6K (p70 S6 kinase) have emerged as critical signaling components in the development of obesity-linked insulin resistance (IR). The pathway is triggered by nutrients and operates a negative feedback loop toward the IRS/PI3K/Akt axis to downregulate insulin's metabolic actions. Recently, some studies have showed that S6K knockdown improves insulin sensitivity in mice fed a high-fat diet (HFD). Here, we tested whether chronic pharmacological S6K1 inhibition can improve insulin sensitivity and glucose metabolism. Mice fed HFD (12 weeks) were treated chronically (7 days) with PF-4708671 (S6K1 inhibitor) (35 mg/kg/day) or RAP (2 mg/kg/day). No significant changes in body weight or food intake were observed. PF-4708671 reduced fasting glucose and improved glucose tolerance in HFD-fed mice, whereas RAP induced fasting hyperglycemia, hyperinsulinemia and glucose intolerance in the same model. Liver, eWAT and muscle tissues were analyzed for insulin signalling and we found that the S6K1 inhibitor increases AKT phosphorylation in HFD mouse while RAP amplifies the disruptive effects of HFD on insulin signalling. In vitro, we observed that hepatocytes (FAO) chronically treated with PF-4708671 (10 uM) had lower basal glucose production, but did not further increase insulin-mediated suppression of glucose production. In L6 myotubes, PF-4708671 was able to increase both basal- and insulin-mediated glucose uptake. Conversely, chronic RAP (25nM) treatment increased hepatic glucose production and decreased glucose uptake. These results suggest that pharmacological S6K1 inhibition may represent a potential therapeutic strategy for combating IR and type 2 diabetes.