A peptide leptin antagonist reduces food intake in rodents

OBJECTIVE: The purpose of the present study was to investigate the continui ng validity of the hypothesis that leptin is a physiologically important re gulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agon istic activity and to competitively inhibit the proliferative effects of le ptin. To determine whether R1280 leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) in to rats in the absence and presence of leptin. R128Q was also injected intr aperitoneally (i.p.) into ob/ob and into db/db mice expressing, respectivel y, either normal or defective ObRb receptors. RESULTS: R1280 was shown to be a competitive antagonist of leptin induced c ellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly les s potent than leptin itself. In fasted rats, the inhibitory effects of lept in and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R1280 leptin produced the same inhibition of food intake as leptin when in jected i.p. in ob/ob mice and, like leptin, was inactive after i.p. injecti on to db/db mice. CONCLUSION: R1280 leptin is a leptin agonist in vivo, but behaves as an ant agonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for inves tigating the physiological actions of leptin.