Soy‐fortelin: A ghrelin sensitivity‐enhancing peptide that stimulates food intake in aged mice

Abstract Ghrelin sensitivity is known to decrease with aging in mice and humans, and the decrease contributes to anorexia with aging. In this study, we discovered novel ghrelin sensitivity‐enhancing peptides. Ghrelin sensitivity was evaluated by examining whether dipeptide samples enhanced the calcium response to ghrelin in the growth hormone secretagogue receptor‐transfected cell line. First, dipeptides were screened using a 336‐dipeptide library and we revealed that Ser‐Tyr (SY) potentiated ghrelin sensitivity in particular. Based on the structure‐activity relationship determined using the dipeptide library and comprehensive analysis of peptides in the chymotrypsin digest of soy β‐conglycinin (β‐CG), which enhanced ghrelin sensitivity, candidate peptides were narrowed down. Among the chemosynthesized peptides, we discovered that an undecapeptide, SLVNNDDRDSY, corresponding to β‐CGα(267‐277), stimulated ghrelin sensitivity in vitro . This peptide enhanced the orexigenic activity of ghrelin in C57BL/6 mice and stimulated food intake. Thus, we demonstrated that SLVNNDDRDSY stimulated ghrelin sensitivity in vitro and in vivo and named it “soy‐ f ortelin”. Moreover, orally administered soy‐ f ortelin had a similar but smaller effect in the young C57BL/6 mice, whereas it strongly stimulated food intake in 2‐year‐old aged mice that exhibited high blood ghrelin levels and low ghrelin sensitivity. In conclusion, we discovered soy‐ f ortelin as a novel peptide that enhances ghrelin sensitivity in vivo and in vitro and increases food intake in young and aged ghrelin‐resistant mice. Soy‐ f ortelin is the first food‐derived peptide reported to enhance ghrelin sensitivity.