A peptide leptin antagonist reduces food intake in rodents

Abstract

OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator 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 agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into oba aob and into dba adb mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in oba aob mice and, like leptin, was inactive after i.p. injection to dba adb mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

Effects of leptin and leptin fragments on steroid secretion of freshly dispersed rat adrenocortical cells

“…Earlier investigations revealed that under various experimental conditions leptin fragments exert biological effects both similar to and distinct from those of the native leptin molecule [7,[19][20][21][22][23][24][25]. Structure-activity studies revealed that two segments of the leptin molecule affect its in vivo and in vitro activities: (1) the N-terminal amino-acid sequence 22-115, which is essential for the biological and receptor-binding activities; and (2) the C-terminal sequence 116-166 possessing a loop structure, that enhances the activity of the N-terminal region.…”

ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin

“…Although these two mutations do not affect the binding to the mouse leptin receptor, they cause reduced biological activity [28]. Of particular, R149Q is unable to trigger intracellular signaling and behaves as a competitive inhibitor [29]. Although Arg-149 has not been predicted part of any of the three binding sites, this residue forms hydrogen bonds with the backbone of Pro-64 (in AB loop) and Val-134 (in helix E).…”

Adipokines as Drug Targets in Diabetes and Underlying Disturbances

“…Indeed, leptin inhibition was shown to have several beneficial effects. A leptin peptide functioning as an antagonist mutant leptin reduced food intake when administered intracerebroventricularly [ 41 ]. Moreover, a leptin antagonist was shown to reverse hypertension induced by leptin central overexpression [ 42 ] and was proposed to be a novel therapeutic approach for the treatment of autoimmune diseases [ 43 ].…”