Inhibition of appetite by nasal leptin administration in rats

Abstract

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. CONCLUSION: 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.

Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents

“…leptin administration. As described previously (8,9), we observed that serum and brain leptin levels increased 30 minutes after i.n. leptin administration.…”

“…Leptin is potentially easy to administer because i.n. leptin administration produces rapid, substantial increases in serum, cerebrospinal fluid, and brain leptin levels (8,9).…”

Leptin Resistance and Obesity

“…The access of various drugs and bioactive substances to the nasal cavity is one useful way to effectively reach the brain [83]. Intranasal leptin administration causes longer suppression of appetite without a significant increase in circulating leptin concentrations in normal Wistar rats [84], suggesting that administration of leptin or analogs into the nasal cavity may be a possible route for leptin administration.…”

Effects of Intranasal Administration of a Leptin-Secreting Lactococcus lactis Recombinant on Food Intake, Body Weight, and Immune Response of Mice

“…Various studies indicate that large molecules, such as peptides, can be directly transported from the nasal mucosa into the cerebrospinal fluid, the olfactory bulb, and the brain parenchyma (30). Several recent studies have shown that intranasal delivery of leptin resulted in the reduction of food intake and body weight (60,61). We observed that intranasal administration of LL-lep significantly reduced food intake and body weight gain compared to administration of LL, suggesting that leptin secreted by LL is biologically active on the central nervous system.…”

“…Since intranasal delivery is an efficient route for the administration of drugs directly to the brain (8,28,37), intranasal leptin administration is considered an interesting strategy to bypass the blood-brain barrier in leptinresistant humans. This has motivated several recent studies demonstrating rapid and effective intranasal leptin administration and transport to the brain (23,60,61). These observations suggest that leptin may still be an effective therapeutic agent for the treatment of obesity (33).…”