Peptide YY3-36 inhibits both anorexigenic proopiomelanocortin and orexigenic neuropeptide Y neurons:: Implications for hypothalamic regulation of energy homeostasis

Peptide YY3-36 (PYY3-36) is released by endocrine cells of the gut and may serve as an important long-distance neuropeptide signal relating energy balance information to the brain to depress food intake. The postulated mechanism is the activation of anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. In striking contrast, using voltage and current-clamp recording, we found that PYY3-36 consistently, dose dependently, and reversibly inhibited POMC cells by reducing action potentials, hyperpolarizing the membrane potential, decreasing input resistance and inward calcium currents, increasing G-protein-gated inwardly rectifying K+ channel currents, and presynaptically inhibiting release of excitatory glutamate. Importantly, we found PYY3-36 had similar inhibitory effects on identified orexigenic neuropeptide Y (NPY) neurons. In both cell types, these effects were blocked by BIIE0246, a Y-2 receptor antagonist. Together, these data argue that anorexigenic actions of PYY3-36 are mediated more likely by inhibition of NPY neurons. Dual PYY3-36 inhibition of both NPY and POMC cells may temporarily reduce the contribution of arcuate cells to feeding circuits, enhancing the role of other CNS loci.