Early-life supplementation of bovine Milk Osteopontin prevents adult obesity by elevating succinic acid and acting through its receptor GPR91.

Early-life nutrition critically programs long-term metabolic health, yet effective interventions to prevent obesity and associated disorders remain limited. Milk osteopontin (OPN) is a bioactive protein naturally present in milk, but its potential of preventing obesity has not been explored. Here, we investigated whether oral administration of bovine milk OPN during early infancy can protect against diet-induced obesity in later life. Mouse pups received bovine milk OPN or vehicle control during the early infancy, followed by a high-fat (HFD) diet challenge after weaning. Early-life OPN administration significantly protected against diet-induced obesity in adulthood. Mechanistically, OPN elevated succinic acid levels in both cecal content and serum in early-life, and upregulated the expression of its receptor GPR91 (succinate receptor 1, SUCNR1) in adipose tissue. Meanwhile, the expression of uncoupling protein (UCP1) and thermogenisis related genes were also increased. Genetic knockout of GPR91 abolished these protective effects, demonstrating that GPR91 is essential for the long-term metabolic benefits of OPN. Collectively, our findings reveal that bovine milk OPN, as a natural milk-derived bioactive protein, can prevent HFD-induced obesity by elelvating succinic acid and acting through the receptor GPR91. This study identifies bovine milk OPN as a promising functional ingredient for early-life nutritional intervention, providing a scientific basis for the development of future obesity prevention strategies.