Peptide YY(3-36) inhibits both anorexigenic proopiomelanocortin and orexigenic neuropeptide Y neurons: implications for hypothalamic regulation of energy homeostasis.
Peptide YY(3-36) (PYY(3-36)) 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 PYY(3-36) 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 PYY(3-36) had similar inhibitory effects on identified orexigenic neuropeptide Y (NPY) neurons. In both cell types, these effects were blocked by BIIE0246, a Y2 receptor antagonist. Together, these data argue that anorexigenic actions of PYY(3-36) are mediated more likely by inhibition of NPY neurons. Dual PYY(3-36) 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.
Acuna-Goycolea
Claudio
C
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
van den Pol
Anthony N
AN
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009478:Neuropeptide Y / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D019894:Peptide YY / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C092926:BIBP 3226; D001514:Bee Venoms; D009478:Neuropeptide Y; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; C062924:neuropeptide Y (13-36); D019894:Peptide YY; C061785:peptide YY (3-36); D049452:Green Fluorescent Proteins; D001464:Barium; C029738:tertiapin; D011333:Pro-Opiomelanocortin; D001120:Arginine