Center of Animal Biotechnology and Gene Therapy, Edifici H, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Diabetologia. 2010 Nov;53(11):2417-30. doi: 10.1007/s00125-010-1840-7. Epub 2010 Jul 10.
AIMS/HYPOTHESIS: In adipocytes, triacylglycerol synthesis depends on the formation of glycerol 3-phosphate, which originates either from glucose, through glycolysis, or from lactate, through glyceroneogenesis. However, glucose is traditionally viewed as the main precursor of the glycerol backbone and thus, enhanced glucose uptake would be expected to result in increased triacylglycerol synthesis and contribute to obesity.
To further explore this issue, we generated a mouse model with chronically increased glucose uptake in adipose tissue by expressing Gck, which encodes the glucokinase enzyme.
Here we show that the production of high levels of glucokinase led to increased adipose tissue glucose uptake and lactate production, improved glucose tolerance and higher whole-body and skeletal muscle insulin sensitivity. There was no parallel increase in glycerol 3-phosphate synthesis in vivo, fat accumulation or obesity. Moreover, at high glucose concentrations, in cultured fat cells overproducing glucokinase, glycerol 3-phosphate synthesis from pyruvate decreased, while glyceroneogenesis increased in fat cells overproducing hexokinase II.
CONCLUSIONS/INTERPRETATIONS: These findings indicate that the absence of glucokinase inhibition by glucose 6-phosphate probably led to increased glycolysis and blocked glyceroneogenesis in the mouse model. Furthermore, this study suggests that under physiological conditions, when blood glucose increases, glyceroneogenesis may prevail over glycolysis for triacylglycerol formation because of the inhibition of hexokinase II by glucose 6-phosphate. Together these results point to the indirect pathway (glucose to lactate to glycerol 3-phosphate) being key for fat deposition in adipose tissue.
目的/假设：在脂肪细胞中，甘油三酯的合成依赖于甘油 3-磷酸的形成，甘油 3-磷酸可以来自葡萄糖，通过糖酵解，也可以来自乳酸，通过甘油酮生成。然而，传统上认为葡萄糖是甘油主链的主要前体，因此，增强葡萄糖摄取应该会导致甘油三酯合成增加，并导致肥胖。
为了进一步探讨这个问题，我们通过表达编码葡萄糖激酶的 Gck 在脂肪组织中产生慢性葡萄糖摄取增加的小鼠模型。
在这里，我们表明高水平的葡萄糖激酶产生导致脂肪组织葡萄糖摄取和乳酸产生增加，葡萄糖耐量改善，全身和骨骼肌胰岛素敏感性提高。体内甘油 3-磷酸合成没有平行增加，脂肪堆积或肥胖。此外，在高葡萄糖浓度下，在过度产生葡萄糖激酶的培养脂肪细胞中，来自丙酮酸的甘油 3-磷酸合成减少，而过度产生己糖激酶 II 的脂肪细胞中的甘油酮生成增加。
结论/解释：这些发现表明，葡萄糖 6-磷酸对葡萄糖激酶的缺乏抑制可能导致小鼠模型中糖酵解增加和甘油酮生成受阻。此外，本研究表明，在生理条件下，当血糖升高时，由于葡萄糖 6-磷酸对己糖激酶 II 的抑制，甘油酮生成可能优先于糖酵解用于甘油三酯的形成。这些结果共同表明，间接途径（葡萄糖到乳酸到甘油 3-磷酸）是脂肪在脂肪组织中沉积的关键。
