Inhibition of appetite by nasal leptin administration in rats.
OBJECTIVE
Leptin inhibits appetite and reduces body weight. However, subcutaneous leptin administration is not very effective on weight reduction. The present studies were undertaken to test the hypotheses that nasally administered leptin effectively accesses to the brain and inhibits appetite.


METHODS
Recombinant leptin (0.5 mg/rat) was administered into the bilateral nasal spaces of rats (i.n.). Changes in serum immunoreactive leptin (IRL) and cerebrospinal fluid (CSF)-IRL concentrations after i.n. leptin administration were compared after intraperitoneal (i.p.) administration. The influence of 0.1 or 0.5% lysophosphatidylcholine (LPC) as an optimizer of leptin absorption was examined. The anorexic effects of i.n. leptin were compared with i.p. leptin in ad libitum fed rats.


RESULTS
The i.n. leptin increased CSF-IRL concentrations, although serum IRL concentrations of rats administered leptin i.n. were lower than those administered i.p. The addition of 0.1 and 0.5% LPC dose-dependently increased serum IRL concentrations, but did not modify CSF-IRL concentrations in i.n. leptin-treated rats. The i.n. leptin inhibited dark-time food consumption at 0-1 h and 3-6 h in ad libitum fed rats. In contrast, i.p. leptin reduced food consumption only for an hour. Phosphorylated signal transducer and activator of transcription (STAT) 3 immunoreactive cells increased in the arcuate nucleus (ARC) of the hypothalamus at 3 h only following i.n. leptin.


CONCLUSIONS
The present study demonstrated that i.n. leptin caused longer inhibition of appetite and phosphorylation of STAT3 in ARC. It is concluded that the trans-nasal route may be useful for the selective access of leptin to the brain in obese people.
Shimizu
H
H
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. hshimizu@showa.gunma-u.ac.jp
Oh-I
S
S
Okada
S
S
Mori
M
M
D000280:Administration, Inhalation; D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects*; D001111:Arcuate Nucleus of Hypothalamus / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000032:analysis; D003864:Depression, Chemical; D020738:Leptin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D008244:Lysophosphatidylcholines / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000032:analysis
D004268:DNA-Binding Proteins; D020738:Leptin; D008244:Lysophosphatidylcholines; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators