Leptin antagonist reveals an uncoupling between leptin receptor signal transducer and activator of transcription 3 signaling and metabolic responses with central leptin resistance.
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.
Scarpace
Philip J
PJ
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA. scarpace@ufl.edu
Matheny
Michael
M
Zhang
Yi
Y
Cheng
Kit-Yan
KY
Tümer
Nihal
N
D050154:Adiposity; D000818:Animals; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics; D004435:Eating; D007031:Hypothalamus / Q000502:physiology; D007473:Ion Channels / Q000032:analysis; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics / Q000502:physiology; D008297:Male; D024101:Mitochondrial Proteins / Q000032:analysis; D010101:Oxygen Consumption; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000502:physiology*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000071256:Uncoupling Protein 1
D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1