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.
Footnotes
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This study was supported by the Medical Research Service of the Department of Veterans Affairs and National Institute on Aging Grants AG-20985 and AG-26159.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112813.
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ABBREVIATIONS: STAT3, signal transducer and activator of transcription 3; PI3, phosphatidylinositol 3; DIO, diet-induced obese; p-STAT3, phosphorylated signal transducer and activator of transcription 3; rAAV, recombinant adeno-associated virus; PWAT, perirenal white adipose tissue; RTWAT, retroperitoneal white adipose tissue; BAT, brown adipose tissue; ANOVA, analysis of variance; WAT, white adipose tissue; UCP1, uncoupling protein 1.
- Received August 23, 2006.
- Accepted October 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics