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Leptin antagonist reveals an uncoupling between leptin receptor signal transducer and activator of transcription 3 signaling and metabolic responses with central leptin resistance.

Abstract
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.
AuthorsPhilip J Scarpace, Michael Matheny, Yi Zhang, Kit-Yan Cheng, Nihal Tümer
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 320 Issue 2 Pg. 706-12 (Feb 2007) ISSN: 0022-3565 [Print] United States
PMID17082312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Ion Channels
  • Leptin
  • Mitochondrial Proteins
  • Receptors, Cell Surface
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Ucp1 protein, rat
  • Uncoupling Protein 1
Topics
  • Adiposity
  • Animals
  • Body Weight
  • Dependovirus (genetics)
  • Eating
  • Hypothalamus (physiology)
  • Ion Channels (analysis)
  • Leptin (antagonists & inhibitors, blood, genetics, physiology)
  • Male
  • Mitochondrial Proteins (analysis)
  • Oxygen Consumption
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred F344
  • Receptors, Cell Surface (physiology)
  • Receptors, Leptin
  • STAT3 Transcription Factor (physiology)
  • Signal Transduction (physiology)
  • Uncoupling Protein 1

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