Shum Michael, Bellmann Kerstin, St-Pierre Philippe, Marette André
Department of Medicine, Quebec Heart and Lung Institute, Hôpital Laval, Pavillon Marguerite d'Youville, Room Y4308, 2705 Chemin Ste-Foy, Québec, Canada, G1V 4G5.
Diabetologia. 2016 Mar;59(3):592-603. doi: 10.1007/s00125-015-3839-6. Epub 2016 Jan 5.
AIMS/HYPOTHESIS: The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo.
We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo.
Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice.
CONCLUSIONS/INTERPRETATION: Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.
目的/假设：雷帕霉素复合物1（mTORC1）/p70核糖体S6激酶（S6K）1通路在肥胖状态下过度激活，导致磷酸肌醇3激酶（PI3K）/Akt信号传导受抑制以及胰岛素抵抗。然而，雷帕霉素对mTORC1的长期抑制会因强烈诱导肝脏糖异生而损害葡萄糖稳态。在此，我们比较了雷帕霉素与选择性S6K1抑制剂PF - 4708671在体外和体内对葡萄糖代谢的影响。
我们使用L6肌细胞和脂肪酸氧化（FAO）肝细胞来探究PF - 4708671对葡萄糖摄取、葡萄糖生成及胰岛素信号传导调节的影响。我们还将PF - 4708671与雷帕霉素对比，对高脂（HF）喂养的肥胖小鼠进行7天治疗，以评估体内的葡萄糖耐量、胰岛素抵抗及胰岛素信号传导。
长期使用雷帕霉素治疗会诱导胰岛素抵抗，并损害肝脏和肌肉细胞中的葡萄糖代谢。相反，用PF - 4708671长期抑制S6K1可降低肝细胞中的葡萄糖生成，并增强肌细胞中的葡萄糖摄取。雷帕霉素治疗会抑制Akt磷酸化，而PF - 4708671在两种细胞系中均可增加Akt磷酸化。mTORC1和S6K1抑制剂的这些相反作用在体内也有观察到。事实上，雷帕霉素治疗会诱导葡萄糖不耐受，且无法改善HF喂养小鼠肝脏和肌肉中的Akt磷酸化，而PF - 4708671治疗可改善这些肥胖小鼠代谢组织中的葡萄糖耐量并增加Akt磷酸化。
结论/解读：PF - 4708671对S6K1的长期抑制通过增强肝脏和肌肉中的Akt激活来改善肥胖小鼠的葡萄糖稳态。我们的结果表明，特异性阻断S6K1是改善肥胖糖尿病个体葡萄糖代谢的一种有效药理学方法。
