Leptin, a protein hormone originating from adipose tissue, circulates in the plasma and affects the energy balance by interacting with the hypothalamus. Leptin plays an important role in the regulation of a variety of physiological functions, including food intake, body temperature and body weight maintenance. Tertiary structure of the leptin molecule reveals the existence of a four-helix bundle that is characteristic of the short-helix cytokines. To identify regions of the leptin molecule responsible for its bioactivity, we have recently synthesized six peptides based on the protein three-dimensional structure. Our results indicated that the fragments Ac-hLEP(92-115)-NH(2) (IV) and Ac-[Ser(117)]-hLEP(116-140)-NH(2) (V) were recognized by leptin receptor present in hp-75 cells validating that this region of the molecule contain the functional epitope of the leptin molecule. In the present study, a new series of decapeptides encompassing the region of fragments IV and V of leptin were synthesized, and their effects on body weight and food intake were assessed when administered into the lateral cerbroventricle of normal rats. Peptides were synthesized by SPPS, purified by RP-HPLC and characterized by LC/ESI-MS. We also performed a conformational study of the peptides by circular dichroism in order to correlate the biological activity and secondary structure of the leptin fragments. Among the fragments tested, we found that Ac-hLEP(110-119)-NH(2) (VI) induce a significant reduction in both body weight and food intake. The use of synthetic leptin-derivate fragments may offer the basis for the development of compounds with potential application in human obesity or to its related metabolic dysfunctions.