Received for publication August 24, 2006.
Revised October 31, 2006.
Accepted for publication October 31, 2006.

Leptin antagonist reveals an uncoupling between leptin receptor STAT3 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 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 rAAV vector encoding leptin by intracerebroventricular injection. Following development of leptin resistance, at day 153, these and control rats were infused centrally either with vehicle or a rat leptin antagonist for 14 days. Food intake, body weight, adiposity and UCP1 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 pre-treated with rAAV-leptin to induce leptin resistance was elevated two-fold. Paradoxically, in these leptin resistant rats, the antagonist fully reversed the two-fold elevated phosphorylated STAT3, but evoked minimal physiological responses. These data reveal an uncoupling between leptin receptor activation and metabolic responses with central leptin resistance.

Key words: STAT3 phosphorylation, central leptin gene therapy, hypothalamic leptin signaling, leptin antagonist, leptin receptor activity, leptin-induced leptin resistance