Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver

Itaconate is an analog of phosphoenolpyruvate, which is an inhibitor of fructose-6-phosphate 2-kinase (F6P2Kinase), an enzyme that synthesizes fructose 2,6-bisphosphate (F26BP). Carbohydrates ingested are preferentially used for glycogen synthesis in the liver and muscles, and excess carbohydrates are metabolized by glycolysis in the liver and used for fatty acid synthesis. We hypothesized that itaconate is incorporated into liver cells and suppresses fat synthesis by inhibiting liver glycolysis at the step of phosphofructokinase, which is activated by F26BP.Rats were allowed to eat ad libitum for 3 wk or, in separate experiments, to limit food intake by pair feeding. One group was given drinking water (control group) and the other group was given a 10 g/L itaconate solution (itaconate group). We measured body weight gain, visceral fat accumulation, and F6P2Kinase activity.Body weight gain in the itaconate group was lower than that in the control group (P < 0.05). In the dietary-controlled rats, there was no difference in body weight increase between groups, but visceral fat content (P < 0.01), plasma free fatty acid, and triacylglycerol levels (P < 0.05) were lower in the itaconate group than in the control group. Further, itaconate decreased the F26BP level (P < 0.05) in vivo and partly inhibited rat liver-type F6P2Kinase in vitro.These results indicate that itaconate, which is a decarboxylate and resembles phosphoenolpyruvate, is incorporated into liver cells and suppresses glycolysis by decreasing the level of F26BP, resulting in decreased visceral fat.