To overcome obesity, new approaches to control energy intake are required. In a dietary preference study in which C57BL/6J male mice were given ad libitum access to two different diets that contained identical %P (Protein), % F (Fat), %C (Carbohydrate) and energy density but differed in their protein sources, mice preferred casein to whey when %P was high (23-33) but as %P fell, an interesting shift in preference was observed from casein to whey. At 23%P, for example, the relative intake of casein was 85.1 2.3% whereas, at 10%P, the relative intake of casein fell to 37.2 2.7% and the intake of whey rose significantly to 62.8 2.7. Interestingly, there was no change in total food intake between 10%P-33%P, demonstrating that energy intake was held constant while the intakes of amino acids was re-balanced. In a separate study similar preference shift observed and did not depend on %C or %F content.
Three amino acids, L-Cys, L-Thr and L-Trp were identified whose intakes were relatively stable during the preference shift and were investigated as candidate modulators of appetite. In particular, supplementation of 10%P casein with L-Cys suppressed food intake to a level comparable to that observed for 10%P whey or 23%P casein. Interestingly, L-Cys also suppressed the fasting plasma level of the candidate appetite modulatory hormone, FGF-21. Thus L-Cys was identified as a limiting amino acid at low %P in casein-based diets (but not whey-based diets) that increased total food intake, presumably secondary to enhanced protein appetite, associated with upregulated production of FGF-21. Selective supplementation of casein with L-Cys or access to an L-Cys-rich protein source (e.g., whey) prevented excess energy intake at low %P diets, overcoming a relative deficiency of L-Cys, which is recognised as a conditionally essential amino acid. The findings have broad implications for studies of dietary protein intake and selection.