Multi-omics analyses revealed the distinct effects of calorie restriction diets with different fat-to-energy ratios on body weight and glycolipid metabolism in rats.

To explore the distinct effects of different fat-to-energy ratio calorie restriction (CR) diets on health, 50 male Wistar rats were randomly assigned to five groups: two ad libitum groups were fed with either normal (ND-AL) or high-fat (HF-AL) diets, and three CR groups were fed with respective low-(10% [cal] fat, LF-CR), medium-(35% [cal] fat, MF-CR) and high-(45% [cal] fat, HF-CR) fat-to-energy ratio diets for 10 weeks after obesity modeling. Among the three CR groups, HF-CR had the most pronounced weight loss effect, but it also exacerbated glycolipid metabolism disorders. In the HF-CR group, an increase in gut microbiota associated with glucose metabolism disorder (e.g., Collinsella and Enterorhabdus) was observed compared to the LF-CR group. Additionally, there was a significant decrease in the expression levels of genes involved in hepatic gluconeogenesis, glycogen synthesis, and insulin signaling in the MF-CR and HF-CR groups when compared to the LF-CR group. Further analysis indicated that Enterorhabdus may potentially regulate the gene expression of the glucokinase regulator (GCKR) by modulating choline metabolism, thereby impacting glucose metabolism. Our study emphasizes the importance of maintaining an appropriate fat-to-energy ratio in CR diets to promote healthy weight loss by balancing dietary fat, gut microbiota, and glucose metabolism.