Dichotomous Effects of Glucose and Fructose on Hepatic Lipogenesis and Insulin Signaling

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for development of obesity, insulin resistance and fatty liver disease. To dissect mechanisms underlying this association, mice were fed chow or HFD with or without addition of fructose- or glucose-supplemented water. There were no physiological differences in mice supplemented with fructose or glucose on chow diet. Despite similar caloric intake, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance and hepatomegaly than glucose-supplemented mice. While both sugars increased Chrebp-?, fructose supplementation uniquely increased Srebp1c and downstream fatty acid synthesis genes resulting in reduced liver insulin signaling, whereas 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 amount of hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese adolescents with steatohepatitis. Knockdown of ketohexokinase-C in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is uniquely associated with poor metabolic outcomes, while increased glucose intake may be protective.

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