P P Nadkarni1, R M Costanzo, M Sakagami. 1. Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, USA.
Abstract
AIMS: Peptide YY (PYY) is an endogenous anorectic gut-secreted peptide that has been shown to suppress appetite in animals and humans, when given by injection. This study tested if needle-free pulmonary delivery of PYY enables food intake suppression and reduced body weight gain in rats. The PYY pharmacokinetics and effects on brain neuropeptide levels were also examined. METHODS: Rats received single or once-daily 7-day pulmonary administration of saline or PYYs. Food intake and body weight gain were monitored to study the effects of different doses (0.08-0.90 mg/kg) of PYY3-36, PYY1-36 and PYY13-36. Plasma PYY pharmacokinetics were determined via enzyme-linked immunosorbent assay. Changes in orexigenic neuropeptide Y (NPY) and c-Fos protein levels in the hypothalamus arcuate nucleus (ARC) were measured by immunofluorescence microscopy. RESULTS: PYY3-36 caused dose-dependent and 4- to 6-h food intake suppression following pulmonary delivery. At 0.80 mg/kg, the effect was significant with 35.1 ± 5.7 and 19.7 ± 4.2% suppression at 4 and 6 h, respectively. Repeated administration for 7 days reduced cumulative body weight gain by 39.4 ± 11.0%. PYY1-36, but not PYY13-36, was equipotent to PYY3-36 in food intake suppression. The plasma PYY concentration reached its peak at 10 min following pulmonary delivery with 12-14% of bioavailability. Increased c-Fos and reduced NPY expressions were observed in the hypothalamus ARC, consistent with the magnitude of food intake suppression by each of the PYYs. CONCLUSIONS: Pulmonary delivery of PYY enabled significant 4- to 6-h food intake suppression via 12-14% of lung absorption and hypothalamic ARC interaction, leading to reduced body weight gain in rats.
AIMS: Peptide YY (PYY) is an endogenous anorectic gut-secreted peptide that has been shown to suppress appetite in animals and humans, when given by injection. This study tested if needle-free pulmonary delivery of PYY enables food intake suppression and reduced body weight gain in rats. The PYY pharmacokinetics and effects on brain neuropeptide levels were also examined. METHODS:Rats received single or once-daily 7-day pulmonary administration of saline or PYYs. Food intake and body weight gain were monitored to study the effects of different doses (0.08-0.90 mg/kg) of PYY3-36, PYY1-36 and PYY13-36. Plasma PYY pharmacokinetics were determined via enzyme-linked immunosorbent assay. Changes in orexigenic neuropeptide Y (NPY) and c-Fos protein levels in the hypothalamus arcuate nucleus (ARC) were measured by immunofluorescence microscopy. RESULTS: PYY3-36 caused dose-dependent and 4- to 6-h food intake suppression following pulmonary delivery. At 0.80 mg/kg, the effect was significant with 35.1 ± 5.7 and 19.7 ± 4.2% suppression at 4 and 6 h, respectively. Repeated administration for 7 days reduced cumulative body weight gain by 39.4 ± 11.0%. PYY1-36, but not PYY13-36, was equipotent to PYY3-36 in food intake suppression. The plasma PYY concentration reached its peak at 10 min following pulmonary delivery with 12-14% of bioavailability. Increased c-Fos and reduced NPY expressions were observed in the hypothalamus ARC, consistent with the magnitude of food intake suppression by each of the PYYs. CONCLUSIONS: Pulmonary delivery of PYY enabled significant 4- to 6-h food intake suppression via 12-14% of lung absorption and hypothalamic ARC interaction, leading to reduced body weight gain in rats.