Endocrine Abstracts

Blockade of the Neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous Peptide YY (3-36) on food intake

CR Abbott, CJ Small, AR Kennedy, NM Neary, A Sajedi, MA Ghatei & SR Bloom

Department of Metabolic Medicine, Imperial College London, London, UK.

The gastrointestinal-derived hormone peptide YY (PYY) is released from intestinal L-cells post-prandially in proportion to calorie intake, and modulates food intake. Peripheral administration of PYY _(3-36) reduces food intake and body weight in rodents and suppresses appetite and food intake in humans. PYY_(3-36) is hypothesised to inhibit food intake via activation of the auto-inhibitory pre-synaptic neuropeptide Y (NPY) Y2 receptor (Y2R) present on arcuate (ARC) NPY neurons. We aimed to investigate the feeding effect of PYY_(3-36) following blockade of ARC Y2R, using the specific receptor antagonist BIIE0246, in the rat. We found that pre-treatment with BIIE0246 (1 nmol) into the ARC attenuated the reduction in feeding observed following intraperitoneal injection of PYY_(3-36)(7.5 nmol/kg) (0-1 h food intake: BIIE0246/ PYY_(3-36): 3.8 plus/minus 0.4 g; vs. Vehicle/ PYY_(3-36): 2.7 plus/minus 0.2 g; p<0.05). We found plasma PYY levels to be maximal at 120 minutes post-initiation of feeding. On investigation of the endogenous role of the Y2R, we found that ARC administration of BIIE0246 alone significantly increased feeding in satiated rats compared to vehicle-injected controls (0-1 h food intake: BIIE0246: 4.1 plus/minus 0.7 g; vs. vehicle: 1.7 plus/minus 0.7 g; p<0.05), suggesting that Y2R antagonism disinhibits the NPY neuron thus stimulating feeding in otherwise satiated rats. These studies suggest that the Y2R plays an important role in post-prandial satiety and provide further insight into the mechanisms of action of PYY_(3-36).

Endocrine Abstracts (2005) 9 OC8