Epitope mapping of secreted mouse leptin utilizing peripherally administered synthetic peptides

We have recently reported that intraperitoneal (ip) administration of synth etic peptide amides corresponding to amino acids 106-140 of mouse leptin si gnificantly reduced food intake and body weight gain in female C57BL/6J ob/ ob mice. These results suggested that leptin activity was localized in doma ins toward its C-terminus between residues 106-140. In the present study, 1 4 overlapping peptides encompassing the complete sequence of secreted mouse leptin were synthesized, and their effects on body weight and food intake in female C57BL/6J ob/ob mice were assessed. When given as seven daily 1-mg ip injections, only peptides corresponding to amino acids 106-120, 116-130 and 126-140 caused significant reductions in body weight and food intake. These results confirmed our earlier study and suggest that in contrast to t he domain encompassed by amino acids 106- 140, the N-terminal of mouse lept in between amino acids 21-105 may not contain functional epitopes that can be utilized as lead compounds in the development of peripherally administer ed bioactive peptide analogs or nonpeptide mimetics of leptin, which may ha ve potential usefulness in treatment of the energy imbalance associated wit h obesity. (C) 1999 Elsevier Science B.V. All rights reserved.