Restricting Isoleucine Intake Reshapes Energy Metabolism and Microecology to Reverse Glucolipid Metabolic Disorders in Perimenopause

Progressive estrogen decline during perimenopause drives glucose and lipid metabolic disorders, raising risks for diabetes and cardiovascular disease. Current therapies like hormone replacement carry safety concerns, creating a need for precise interventions. Using aged perimenopausal mice, this study applied an isoleucine-restricted diet, which reversed weight gain, insulin resistance, hepatic steatosis, and inflammation. Its core innovation is an integrated “diet-gut microbiota-host metabolism” model: the diet enriched beneficial bacteria like Ligilactibacillus murinus, elevating SCFAs (acetate/propionate). These SCFAs repaired gut barrier integrity, inhibited NF-κB, and synergistically modulated PI3K/AKT, mTOR, and AMPK pathways to restore metabolic homeostasis. This study first confirms the diet’s value in estrogen-deficient perimenopause, breaking traditional calorie restriction limits, and provides novel targets for precise nutritional intervention, with significant theoretical and clinical transformation potential.