Endocrine Abstracts

Peptide YY (PYY) is a satiety hormone that communicates nutritional status to the central nervous system. PYY is released postprandially from endocrine L-cells in proportion to calories consumed. It is processed to generate the principle bioactive form PYY3–36, which acts on Y2 receptors in feeding centres within the brainstem and hypothalamus to reduce appetite. Chronic intravenous infusion of PYY3–36 induces weight loss in rodents, and obese humans display low plasma PYY levels, suggesting PYY3–36 may be a useful anti-obesity drug target. However, PYY3–36 has a short biological half-life. Previously, zinc metalloendopeptidases concentrated in kidney brush border (KBB) have been implicated in PYY degradation. Renal failure patients exhibit high levels of PYY3–36 and reduced appetite. Thus we hypothesised that the kidney may be a primary site of PYY3–36 clearance. This was investigated by comparing the pharmacokinetics of exogenous PYY3–36 in nephrectomised and sham-operated rats. The half-life of PYY3–36 was increased from 25.9 (±0.03) to 45.4 (±0.7) min in nephrectomised rats versus sham-operated controls. To further investigate the metabolic profile of PYY3–36, both purified metalloendopeptidase meprin β and KBB preparations were incubated with PYY3–36 in vitro and the cleavage products analysed by high performance liquid chromatography (HPLC) and mass spectrometry. Both meprin β and KBB membranes appeared to cleave PYY3–36 between the negatively charged residues Glu10-Asp11. When KBB was pretreated with the meprin β inhibitor actinonin, the breakdown of PYY3–36 by KBB was entirely prevented. Furthermore, mice administered actinonin with PYY3–36 displayed a significant increase in PYY3–36 plasma levels at 20 and 60 min post-injection compared to mice administered PYY3–36 only. These experiments have begun to elucidate the mechanisms responsible for the breakdown of PYY3–36 in vivo, providing data useful in the development of long-acting PYY analogues for the treatment of obesity.