Protein‐leverage in Mice: The Geometry of Macronutrient Balancing and Consequences for Fat Deposition

Abstract

The Protein-Leverage Hypothesis proposes that humans regulate their intake of macronutrients and that protein intake is prioritized over fat and carbohydrate intake, causing excess energy ingestion when diets contain low %protein. Here we test in a model animal, the mouse: (i) the extent to which intakes of protein and carbohydrate are regulated; (ii) if protein intake has priority over carbohydrates so that unbalanced foods low in %protein leads to increased energy intake; and (iii) how such variations in energy intake are converted into growth and storage. We fed mice one of five isocaloric foods having different protein to carbohydrate composition, or a combination of two of these foods (N = 15). Nutrient intake and corresponding growth in lean body mass and lipid mass were measured. Data were analyzed using a geometric approach for analyzing intake of multiple nutrients. (i) Mice fed different combinations of complementary foods regulated their intake of protein and carbohydrate toward a relatively well-defined intake target. (ii) When mice were offered diets with fixed protein to carbohydrate ratio, they regulated the intake of protein more strongly than carbohydrate. This protein-leverage resulted in higher energy consumption when diets had lower %protein and led to increased lipid storage in mice fed the diet containing the lowest %protein. Although the protein-leverage in mice was less than what has been proposed for humans, energy intakes were clearly higher on diets containing low %protein. This result indicates that tight protein regulation can be responsible for excess energy ingestion and higher fat deposition when the diet contains low %protein.