Mice regulate dietary amino acid balance and energy intake by selecting between complementary protein sources

Background A balanced intake of protein and constituent amino acids (AAs) requires adjustments to total food intake (protein leverage; PL); and (ii) food selection to balance deficits and excesses (complementary feeding). We provided mice with choices of Casein and Whey, two protein sources that are complementary in AA balance, across a range of protein concentrations (P%) of digestible energy (DE). Objectives We determined whether: PL operates similarly for Casein and Whey; one protein source is preferred at control P%; the preference changes as P% falls; and whether AA intakes under control and low P% levels identify AAs that drive changes in protein selection. Methods Food intake and plasma FGF21 levels were studied in mice at various P% (7.5%–33%). For direct comparisons, defined diets were used in which the protein source was either Casein or Whey. In food choice studies, mice had access to foods in which both Casein and Whey were provided at the same P% level at the same time. Results PL operated at different P% thresholds in Casein (13%)- and Whey (10%)-based diets and the magnitude of PL was greater for Casein. Although mice preferred Casein under control conditions (P23%), a pronounced preference shift to Whey occurred as P% fell to 13% and 10%. At low P%, increases in food intake were accompanied by increases in plasma FGF21, a protein hunger signal. Among AAs deficient in casein and enriched in whey, the intake of cysteine was the most invariant as P% changed between P23% and P10%, appearing to drive the switch in protein preference. Conclusions Mice selected between complementary protein sources, Casein and Whey, achieving stable total energy intake and regulated intake of amino acids as P% varied. Supplementation of low P% casein diets with one Whey-enriched AA, Cysteine, suppressed plasma FGF21 and total food intake.