The soluble leptin receptor neutralizes leptin-mediated STAT3 signalling and anorexic responses in vivo.
OBJECTIVE
The soluble leptin receptor (SLR) is the major, circulating, leptin-binding protein and, in vitro, the SLR inhibits leptin-binding to cell surface receptors. Here we assessed the effects of the SLR on physiological responses to leptin, in vivo.


METHODS
SLR and leptin were given as a single injection (intracerebroventricularly, i.c.v.) or by central (i.c.v.) and peripheral (s.c.) infusion to normal adult F344XBN rats. Phosphorylation of hypothalamic STAT3 (Western blot), food intake and body weight, and the thermogenic response in brown adipose tissue (BAT) were measured.


RESULTS
Acute central co-administration of SLR (13.5 microg) and leptin (90 ng) blocked the threefold increase in hypothalamic STAT3 phosphorylation induced by leptin alone, 1 h after the injections. Peripheral leptin infusion (0.1 mg day(-1) for 7 days; s.c.) induced a significant reduction in food intake and body weight, which were partially blocked with a simultaneous central infusion of SLR (4.3 microg day(-1); i.c.v.). In a second experiment, SLR central infusion alone (5.5 microg day(-1)) increased food intake and body weight, suggesting that the SLR was able to neutralize endogenous leptin in the brain. This dose of SLR, infused together with a lower dose of peripheral leptin (0.05 mg day(-1)), abolished the thermogenic response in BAT, but the anorexic responses and weight reduction were only partially attenuated.


CONCLUSIONS
These results provide direct evidence that the SLR neutralizes leptin, endogenous or exogenous, in vivo. By neutralizing leptin, the SLR may play a regulatory role in energy homeostasis.
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610, USA.
Jiejin
J
Zhang
Philip J
PJ
Scarpace
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D054411:Receptors, Leptin / Q000008:administration & dosage / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat