PT  - JOURNAL ARTICLE
AU  - Philip J. Scarpace
AU  - Michael Matheny
AU  - Yi Zhang
AU  - Kit-Yan Cheng
AU  - Nihal Tümer
TI  - Leptin Antagonist Reveals an Uncoupling between Leptin Receptor Signal Transducer and Activator of Transcription 3 Signaling and Metabolic Responses with Central Leptin Resistance
AID  - 10.1124/jpet.106.112813
DP  - 2007 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 706--712
VI  - 320
IP  - 2
4099  - http://jpet.aspetjournals.org/content/320/2/706.short
4100  - http://jpet.aspetjournals.org/content/320/2/706.full
SO  - J Pharmacol Exp Ther2007 Feb 01; 320
AB  - Leptin-resistant rats have reduced leptin receptors and signaling and are refractory to exogenous leptin. However, it is unclear how leptin-mediated hypothalamic signal transducer and activator of transcription 3 (STAT3) signaling relates to the loss of physiological responsiveness. We hypothesized that if leptin resistance is associated with leptin receptors that are no longer functionally coupled to leptin responses, then a leptin antagonist should be less effective in leptin-resistant compared with leptin-responsive rats. Hypothalamic leptin resistance was induced in lean rats with a recombinant adeno-associated viral (rAAV) vector encoding leptin by intracerebroventricular injection. Following development of leptin resistance, at day 153, these rats and control rats were infused centrally either with vehicle or a rat leptin antagonist for 14 days. Food intake, body weight, adiposity, and uncoupling protein 1 expression increased with antagonist infusion in controls but elevated only marginally in leptin-resistant rats. Basal hypothalamic STAT3 signaling remained unchanged with antagonist infusion in control rats despite the pronounced orexigenic response in these animals. STAT3 phosphorylation in rats pretreated with rAAV-leptin to induce leptin resistance was elevated 2-fold. Paradoxically, in these leptin-resistant rats, the antagonist fully reversed the 2-fold elevated phosphorylated STAT3, but it evoked minimal physiological responses. These data reveal an uncoupling between leptin receptor activation and metabolic responses with central leptin resistance. The American Society for Pharmacology and Experimental Therapeutics