Integrated Remodeling of Gut–Liver Metabolism Induced by Moderate Protein Restriction Contributes to Improvement of Insulin Sensitivity

SCOPE: Protein restriction (PR) is beneficial for relieving metabolic disorders and aging‐related diseases. However, extreme PR could result in malnutrition due to severe deficiency of essential amino acids. Therefore, the effect of moderate PR on insulin sensitivity is investigated. METHODS AND RESULTS: The growing and adult pigs are subjected to moderate PR by 15–30%. Plasma insulin concentration and insulin resistance index HOMA‐IR are significantly decreased upon moderate PR. Furthermore, IRS1/PI3K/AKT pathway in the basal state is enhanced in both liver and skeletal muscle. The adapted metabolism in the liver upon moderate PR is in support of improving insulin sensitivity. The liver shares a coordinated metabolic adaption in terms of energy metabolism and amino acid metabolism with the small intestine. Particularly, alteration of the metabolic footprint appeared in the portal venous blood, representing metabolites to be absorbed into liver after intestinal metabolism, is also in favor of improvement of insulin sensitivity. CONCLUSION: In summary, the study proves that moderate PR could improve insulin sensitivity from childhood to adulthood in a pig model, and sheds a new light on the role of integrated remodeling of gut and liver metabolism in the improved insulin sensitivity induced by moderate PR.