Pulmonary delivery of peptide YY for food intake suppression and 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.