title: Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons.
abstract: Glucagon-like peptide 1 (GLP-1) is a potent inhibitor of food intake. GLP-1 receptor mRNA is densely expressed in hypothalamic arcuate nucleus (ARC) and precisely overlaps the area occupied by proopiomelanocortin (POMC) neurons. Activation of POMC neurons suppresses appetite, and lack of POMC-derived peptides or inhibition of POMC neuronal firing causes obesity. Here, we identify living POMC cells in mouse ARC brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that GLP-1 increases the spontaneous action-potential firing of POMC neurons. The stimulatory effect of GLP-1 was mimicked by GLP-1 receptor agonist exendin-4 and abolished by the receptor antagonist exendin 9-39. The effect of GLP-1 was unchanged in the presence of the synaptic blockers DAP5 (D(-)-2-amino-5-phosphonopentanoic acid)/CNQX (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt) and picrotoxin. These results suggest that GLP-1 excites POMC neurons postsynaptically, via interaction with GLP-1 receptors on POMC cells. Whole-cell Ca2+ currents increased approximately 70% in the presence of GLP-1, and this effect was abolished by L-type Ca2+ channel antagonist nifedipine. Forskolin (which activates cAMP) mimicked the effects of GLP-1 and the PKA inhibitor Rp-8-Bromo-cAMPS (8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer) blocked GLP-1 action. These data indicate that GLP-1 stimulates the electrical activity of hypothalamic POMC neurons by activation of PKA and a subsequent increase in L-type Ca2+ current. This effect may contribute to the anorectic action of GLP-1, because excitation of POMC cells is well established to reduce food intake.
authors.affiliation: University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
authors.forename: Jens
authors.initials: J
authors.lastname: Bruning
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004553:Electric Conductivity; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000502:physiology*; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D011333:Pro-Opiomelanocortin; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases