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.