Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
Life Sci. 2017 Feb 1;170:50-55. doi: 10.1016/j.lfs.2016.11.027. Epub 2016 Nov 30.
To investigate the role of glucose and insulin in the regulation of hepatic fat mass and obesity associated (Fto) gene expression and the role of hepatic Fto in the regulation of gluconeogenic gene expression.
To determine the effect of hyperglycemia on hepatic Fto expression, levels of Fto mRNA in liver were compared between normoglycemic/normoinsulinemic, hypereglycemic/hyperinsulinemic, and hyperglycemic/hypoinsulinemic mice. To determine the direct effect of insulin on Fto expression, levels of Fto, glucose-6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (Pepck) mRNA levels were compared between control and insulin-treated mouse liver tissues cultured ex vivo and immortalized mouse hepatocytes AML12. To determine the role of Fto in the regulation of gluconeogenic gene expression, we examined the effect of enhanced Fto expression on G6pase and Pepck mRNA levels in AML12 cells.
Fto mRNA levels were significantly reduced in hyperglycemic/hyperinsulinemic mice compared to normoglycemic/normoinsulinemic mice, while they were indistinguishable between hyperglycemic/hypoinsulinemic mice and normoglycemic/normoinsulinemic mice. Insulin treatment reduced Fto, G6pase, and Pepck mRNA levels compared to control vehicle treatment in both ex vivo cultured mouse liver tissues and AML12 cells. Enhanced Fto expression significantly increased G6pase and Pepck mRNA level in AML12 cells.
Our findings support the hypothesis that hepatic Fto participates in the maintenance of glucose homeostasis possibly by mediating the inhibitory effect of glucose and insulin on gluconeogenic gene expression in liver. It is further suggested that impairments in nutritional and hormonal regulation of hepatic Fto expression may lead to impairments in glycemic control in diabetes.
研究葡萄糖和胰岛素在调节肝脂肪量和肥胖相关（Fto）基因表达中的作用，以及肝 Fto 在调节糖异生基因表达中的作用。
为了确定高血糖对肝 Fto 表达的影响，比较了正常血糖/正常胰岛素血症、高血糖/高胰岛素血症和高血糖/低胰岛素血症小鼠的肝 Fto mRNA 水平。为了确定胰岛素对 Fto 表达的直接影响，比较了体外培养的对照和胰岛素处理的小鼠肝组织以及永生化的小鼠肝细胞 AML12 中 Fto、葡萄糖-6-磷酸酶（G6pase）和磷酸烯醇丙酮酸羧激酶（Pepck）mRNA 水平。为了确定 Fto 在调节糖异生基因表达中的作用，我们研究了增强 Fto 表达对 AML12 细胞中 G6pase 和 Pepck mRNA 水平的影响。
与正常血糖/正常胰岛素血症小鼠相比，高血糖/高胰岛素血症小鼠的 Fto mRNA 水平显著降低，而高血糖/低胰岛素血症小鼠与正常血糖/正常胰岛素血症小鼠之间无差异。与对照载体处理相比，胰岛素处理可降低体外培养的小鼠肝组织和 AML12 细胞中 Fto、G6pase 和 Pepck mRNA 水平。增强 Fto 表达可显著增加 AML12 细胞中 G6pase 和 Pepck mRNA 水平。
我们的研究结果支持这样的假说，即肝 Fto 参与维持葡萄糖稳态，可能是通过介导葡萄糖和胰岛素对肝糖异生基因表达的抑制作用。进一步表明，营养和激素调节肝 Fto 表达的损伤可能导致糖尿病患者血糖控制受损。
