RT Journal Article
SR Electronic
T1 Leptin Antagonist Reveals an Uncoupling between Leptin Receptor Signal Transducer and Activator of Transcription 3 Signaling and Metabolic Responses with Central Leptin Resistance
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 706
OP 712
DO 10.1124/jpet.106.112813
VO 320
IS 2
A1 Philip J. Scarpace
A1 Michael Matheny
A1 Yi Zhang
A1 Kit-Yan Cheng
A1 Nihal Tümer
YR 2007
UL http://jpet.aspetjournals.org/content/320/2/706.abstract
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