NPY presynaptic actions are reduced in the hypothalamic mpPVN of obese (fa/fa), but not lean, Zucker rats in vitro

1 Neuropeptide Y (NPY) profoundly enhances feeding when injected intracerebroventricularly, or directly into hypothalamic nuclei, such as the paraventricular nucleus (PVN). Paradoxically, NPY has a reduced action on feeding in obese Zucker rats relative to lean Zucker rats, although the obese rats have much higher levels of hypothalamic NPY expression. GABAergic inputs to a subpopulation of medial parvocellular PVN (mpPVN) neurons are sensitive to NPY. Here, we tested the hypothesis that the blunted eating response to NPY observed in obese Zucker rats will be reflected in a reduced NPY action at mpPVN GABAergic synapses. 2 'Blind' whole-cell patch-clamp recordings made from mpPVN neurons in acute brain slices of lean and obese Zucker rats revealed GABAergic inhibitory postsynaptic currents (IPSC) responses which were inhibited by NPY. While the maximum response in the obese Zucker rats was significantly less than in lean Zucker or Sprague-Dawley rats, there was no difference in the EC50. 3 Experiments using blocking concentrations of Y-1- or Y-5-receptor antagonists revealed no differences between lean and obese Zucker rats in the contributions of either of these receptors to the total NPY response in mpPVN. 4 NPY is less effective at the mpPVN GABA synapse in obese than in lean Zucker rats. This is not associated with a change in the proportion of Y-1 or Y-5 receptors mediating the NPY response, and is consistent with the downregulation of NPY receptors or a reduction in receptor-effector coupling, and with the reduced sensitivity of obese rats to NPY.