Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice

Abstract

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.ketohexokinase | hepatic steatosis | insulin | leptin

Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway

“…Without negative feedback mechanisms, metabolic flow of fructose through this pathway remains largely unregulated and greatly exceeds energy demands (4,7). This causes dramatic stimulation of lipogenesis and fat accumulation in the liver, Recently, Ishimoto et al (10) demonstrated that fructoseinduced, abnormal lipogenesis in the liver, hepatosteatosis, triglyceridemia, and visceral obesity were absent in mice lacking both isoforms of KHK. While consuming similar amounts of fructose, KHK-deficient mice were excreting substantial amounts of it with urine but still maintained positive energy balance but on the lower level than wild-type (WT) mice fed with fructose (10).…”

Bellagio Report on Healthy Agriculture, Healthy Nutrition, Healthy People

“…We use the apparent self-contradiction, -a calorie is not a calorie‖, to emphasize that different nutrients with the same amount of food energy (calories) can differ in their effects on body weight. Fructose, for example, increases appetite more effectively than glucose [20,26]. One calorie of fructose is therefore more obesogenic than one calorie of glucose.…”

Bioactivity-guided identification of botanical inhibitors of ketohexokinase

“…As a major component of added sugars, high intake of fructose has been shown to cause numerous adverse metabolic effects, suggesting that it has a contributory role in the development of obesity and metabolic syndrome [6][7][8]. Administration of added sugars or fructose has been shown to induce all of the features of metabolic syndrome in rats and in humans, such as hypertriglyceridemia and lipogenesis, increased blood pressure, fatty liver, and visceral fat accumulation [9][10][11]. Fructose has also been shown to impair insulin sensitivity, injure β-islet cells, and cause lactic acidosis, oxidative stress, and kidney injuries in animals [12][13][14][15][16][17][18][19].…”