Tea polyphenol EGCG enhances the improvements of calorie restriction on hepatic steatosis and obesity while reducing its adverse outcomes in obese rats

• EGCG enhanced the improvements of calorie restriction (CR) on hepatic steatosis and obesity in LepR KO rats. • EGCG reduced the adverse outcomes of CR on LepR KO rats, especially in hepatic lipogenesis and maintaining homeostasis of gut microbiota. • CR plus EGCG more significantly regulates glycerophospholipid, glycerolipid and sphingolipid metabolism to improve dyslipidemia in LepR KO rats than CR alone. • CR plus EGCG effectively activated the SIRT6/SREBP1/FAS pathway to reduce hepatic lipid accumulation. Currently, calorie restriction (CR) is popular among young people as a way to lose weight and prevent obesity. However, CR can also cause a series of side effects, such as weight regain after resuming free eating. Tea polyphenol epigallocatechin-3-gallate (EGCG) has been widely recognized as antiobesity effects. However, whether EGCG can enhance the antiobesity effect of CR and reduce its adverse outcomes is still unclear. This study aimed to explore the enhancing effect and molecular mechanism of EGCG supplementation on CR in improving hepatic steatosis and obesity. The enhancing effect and molecular mechanism of EGCG supplementation on CR in alleviating hepatic steatosis and obesity were explored using a leptin receptor-knockout (LepR KO) rat model by performing biochemical, histochemistry, qPCR, plasma lipidomic, and gut microbiota analysis. Our results showed that CR plus EGCG exhibited enhanced preventive effects in reducing blood glucose, insulin, TC, TG, LDL-C, and FFA levels in plasma, and protection against hepatic steatosis in LepR KO rats than CR alone. In addition, CR plus EGCG remarkably reduced oxidative stress and systemic inflammatory responses in LepR KO rats. Moreover, the combined intervention showed an enhanced improvement effect on the homeostasis of gut microbiota than CR alone, including increasing gut microbiota diversity and modulating microbiota composition. Plasma lipidomics analysis showed that CR plus EGCG significantly improved glycerophospholipid, glycerolipid and sphingolipid metabolism in LepR KO rats. Mechanistic studies showed that CR combined EGCG enhanced SIRT6 and suppressed SREBP1 and FAS expression in the livers of LepR KO rats than CR alone, thereby improving host lipid metabolism. This study demonstrated that EGCG enhance the improvements of CR on hepatic steatosis and obesity in LepR KO rats, and reduce its adverse outcomes, especially in reducing hepatic lipogenesis and maintaining homeostasis of gut microbiota. This study provides a dietary strategy for preventing weight rebound following the transition from CR to a free diet by supplementing EGCG, suggesting that CR plus EGCG may offer a promising therapy for managing obesity in humans.