Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

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葡萄糖和果糖对肝脏脂肪生成和胰岛素信号传导的不同作用

高脂饮食（HFD）和含糖饮料的过度消费是肥胖，胰岛素抵抗和脂肪肝疾病的危险因素。在这里，我们使用饲料或高脂饮食加或不加果糖或葡萄糖补充水的小鼠解剖了这种关联的机制。在用粗饲料喂养的小鼠中，果糖和葡萄糖补充剂之间没有重大的生理差异。另一方面，尽管补充了类似的卡路里，但补充了果糖的HFD小鼠与补充葡萄糖的HFD小鼠相比，肥胖，葡萄糖耐受不良和肝肿大更为明显。果糖和葡萄糖补充剂也对脂肪形成转录因子ChREBP和SREBP1c的表达具有明显的影响。虽然两种糖都增加了ChREBP-β，果糖补充独特地增加了SREBP1c和下游脂肪酸合成基因，从而降低了肝脏胰岛素信号传导。相反，葡萄糖增强了ChREBP的总表达和甘油三酸酯的合成，但与改善的肝胰岛素信号传导有关。代谢组学和RNA序列分析证实，尽管诱导了相似的肝脂质蓄积，但果糖和葡萄糖补充对肝代谢的二分作用。酮己糖激酶是果糖代谢的第一种酶，在果糖喂养的小鼠和患有脂肪性肝炎的肥胖人群中升高。敲除肝脏中的酮己糖激酶可以改善果糖补充小鼠的肝脂肪变性和葡萄糖耐量。因此，果糖是膳食糖的一个组成部分，与不良的代谢结果明显相关，