A Moderately High-Protein Diet During the Critical Development Period Protects Hepatic Functional Integrity and...

A high-protein diet (HP) in early life has long-term effects on the metabolism and liver health of offspring. However, few studies focus on the impact of early nutritional status on the more disease-susceptible midlife period. Here, we elucidate a moderately HP during critical development and the underlying mechanisms for liver function and metabolic health in middle-aged offspring. Pregnant Wistar rats are given a 6-week dietary intervention with a control diet and a moderately HP during gestation and lactation. The maternal high-protein diet (mHP) group increases energy expenditure, preventing liver fat accumulation and alleviating systemic inflammation of middle-aged offspring. Additionally, the mHP group reshapes offspring gut microbiota, significantly increasing the abundance of Clostridia_vadinBB60_group, Ruminococcaceae_UBA1819, Flavonifractor, and Butyricicoccaceae_UCG-009. Metabolomics and transcriptomics reveal that mHP maintains energy homeostasis in middle-aged offspring by altering serum amino acid, organic acid, and fatty acid profiles and activating the hepatic AMPK/SREBP-1c pathway to preserve liver integrity via the gut-liver axis. We also demonstrate in the Drosophila model that mHP increases AMPK levels and alleviates lipid accumulation in the gut and fat body of middle-aged flies. These findings provide valuable insights into the pivotal role of prenatal nutrition in offspring's long-term health.